Modified release gamma- hydroxybutyrate formulations having improved pharmacokinetics

ABSTRACT

Modified release formulations of gamma-hydroxybutyrate having improved dissolution and pharmacokinetic properties are provided, and therapeutic uses thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/655,924, filed Jul. 21, 2017, which claims priority to U.S.Provisional Application No. 62/365,812, filed Jul. 22, 2016, U.S.Provisional Application No. 62/399,413, filed Sep. 25, 2016, and U.S.Provisional Application No. 62/474,330, filed Mar. 21, 2017.

FIELD OF THE INVENTION

The present invention relates to modified release formulations ofgamma-hydroxybutyrate having improved pharmacokinetic (PK) properties,and to therapeutic uses thereof.

BACKGROUND

Narcolepsy is a devastating disabling condition. The cardinal symptomsare excessive daytime sleepiness (EDS), cataplexy (a sudden loss ofmuscle tone triggered by strong emotions, seen in approximately 60% ofpatients), hypnogogic hallucination (HH), sleep paralysis (SP), anddisturbed nocturnal sleep (DNS). Other than EDS, DNS is the most commonsymptom seen among narcolepsy patients.

The diagnosis of narcolepsy rests in part on clinical grounds. Whennarcolepsy is suspected, it is standard practice to administer anovernight polysomnogram (PSG) followed by a multiple sleep latency test(MSLT) to document the rapid eye movement (REM) abnormality thatcharacterizes the disorder. On the MSLT a mean sleep latency less thanor equal to 8 minutes and two or more sleep onset REM periods (SOREMPs)are required to confirm a diagnosis of Type 1 or Type 2 narcolepsy. Itis also possible, but infrequently preferred, that narcolepsy bediagnosed by measuring hypocretin in the cerebrospinal fluid (CSF) incases where the PSG and/or MSLT is not completed. For these cases, ahypocretin concentration of less than 110 pg/nL confirms a narcolepsyType 1 diagnosis.

One of the major treatments for narcolepsy is sodium oxybate, aneuroactive agent with a variety of Central Nervous System (CNS)pharmacological properties. The species is present endogenously in manytissues, where it acts as a neurotransmitter on a gamma-hydroxybutyrate(GHB) receptor (GHBR), and possesses neuromodulatory properties withsignificant effects on dopamine and gamma-Aminobutyric Acid (GABA).Studies have suggested that sodium oxybate improves Rapid Eye MovementSleep (REM sleep, REMS) of narcoleptics in contrast to antidepressantdrugs.

Sodium oxybate is also known as sodium 4-hydroxybutanoate, orgamma-hydroxybutyric acid sodium salt, and has the following chemicalstructure:

Sodium oxybate is marketed commercially in the United States as Xyrem®.The product is formulated as an immediate release liquid solution thatis taken once immediately before bed, and a second time approximately2.5 to 4 hours later, in equal doses. Sleep-onset can be dramatic andfast, and patients are advised to be sitting in bed when consuming thedose. The most commonly reported side effects are confusion, depressivesyndrome, incontinence and sleepwalking.

When initiating treatment with sodium oxybate, careful titration up toan adequate level is essential both to obtain positive results and avoidadverse effects. The recommended starting dose is 4.5 g divided into 2equal doses of 2.25 g, the first taken at bedtime and the second taken2.5 to 4 hours later. The starting dosage can be decreased to 3.0 g/dayor increased to as high as 9.0 g/day in increments of 1.5 g/day (0.75 gper dose). Two weeks are recommended between dosage adjustments tooptimize reduction of daytime symptoms and minimize side effects. Theideal dose will provide an effective eight hours of sleep but, at theend of eight hours, very little of the drug will remain in the patient'sbloodstream to affect the patient's wakefulness.

The requirement to take Xyrem® twice each night is a substantialinconvenience to narcolepsy patients. The patient must typically set analarm to take the second dose, which can interrupt ongoing productivesleep. Several efforts have been made to provide a once-nightly modifiedrelease dosage form of sodium oxybate, but none has yet receivedapproval from the United States Food and Drug Administration (“FDA”) orproven effective in the clinic.

One of the biggest drawbacks of these once-nightly formulations is thereduction in bioavailability that occurs when sodium oxybate isformulated in a modified release dosage form, as measured by the bloodconcentration/time area under the curve (“AUC”). U.S. 2012/0076865 A1 byAllphin et al. (“Allphin”), for example, conducted two separatecrossover bioavailability trials involving three separate modifiedrelease formulations and an immediate release solution, and reported thefollowing bioavailability results:

AUClast AUCinf λ_z T_(1/2) Cmax (hr * (hr * (1/hr) (hr) Tmax (hr)^(a)(ug/ml) ug/ml) ug/ml) Summary of PK Parameters for Treatments A, B, CTreatment A N 29 29 29 29 29 29 Mean 1.22 0.6 4.50 (0.5, 4.75) 130.79350.84 351.2 SD 0.27 0.13 31.52 116.74 116.74 CV % 21.93 22.61 24.133.27 33.24 Mean 1.19 0.58 127.3 333.33 333.72 Treatment B N 18 18 19 1919 18 Mean 0.62 1.22 2.00 (1.50, 5.00) 41.78 188.23 196.25 SD 0.16 0.4018.40 103.60 102.50 CV % 26.44 32.58 44.03 55.04 52.23 Mean 0.59 1.1738.46 163.80 173.33 Treatment C N 19 19 19 19 19 19 Mean 0.74 0.99 2.50(1.00, 5.00) 50.49 221.64 222.60 SD 0.16 0.23 15.83 106.85 106.80 CV %22.25 22.93 31.35 48.21 47.98 Mean 0.72 0.96 48.10 200.08 201.12 Summaryof OK Parameters for Treatments A, D, E Treatment A N 30 30 30 30 30 30Mean 1.08 0.71 4.50 (0.50, 5.50) 114.59 301.28 301.59 SD 0.31 0.27 27.91100.85 100.87 CV % 29.00 37.90 24.36 33.47 33.45 Mean 1.03 0.67 111.20285.47 285.79 Treatment D N 30 30 30 30 30 30 Mean 0.46 1.63 0.75 (0.50,2.50) 25.10 64.44 65.58 SD 0.14 0.47 7.33 20.36 20.26 CV % 30.27 29.0029.20 31.60 30.90 Mean 0.44 1.56 24.10 61.31 62.55 Treatment E N 30 3030 30 30 30 Mean 0.59 1.36 1.00 (0.50, 5.00) 59.52 242.30 243.80 SD 0.200.64 17.72 117.15 116.79 CV % 34.57 46.91 29.77 48.35 47.91 Mean 0.551.25 56.89 216.33 218.12 Treatment A: Two 3 g IR doses administered fourhours apart Treatment B: One 6 g CR dose administered at time zero (noIR component) Treatment C: One 6 g CR dose administered at time zero (noIR component) Treatment D: One 4 g dose including IR and CR fractionsadministered at time zero Treatment E: One 8 g dose including IR and CRfractions administered at time zero

As can be seen, mean AUC_(inf), which measures the total exposure of thebody to sodium oxybate for a given dose, was significantly less for thedoses having a modified release component when compared to the immediaterelease doses. Mean AUC_(inf) for Treatment B, which included the exactsame dose of sodium oxybate as Treatment A, was only 56% of the meanAUC_(inf) for Treatment A; mean AUC_(inf) for Treatment C, which alsoincluded the same dose of sodium oxybate as Treatment A, was only 63% ofthe mean AUC_(inf) for Treatment A; mean AUC_(inf) for Treatment E wasonly 81% of the mean AUC_(inf) of Treatment A, even though Treatment Edosed 2 g more of sodium oxybate than Treatment A, which, compared tosame dose, represented only 61% of the mean AUC_(inf) of Treatment A.Mean AUC_(inf) for Treatment D was only 22% of the mean AUC_(inf) ofTreatment A, although Treatment D dosed 2 g less of sodium oxybate thanTreatment A, which, compared to same dose, represented only 33% of themean AUC_(inf) of Treatment A. As shown in FIGS. 12 and 14 of U.S.2012/0076865 A1, Allphin's formulations also suffered from an excess ofsodium oxybate remaining in the bloodstream at 8 hours.

U.S. Pat. No. 8,193,211 to Liang et al. (“Liang”) reports even lowerbioavailability from his once-nightly formulations. Liang developedseveral enterically coated delayed release formulations of sodiumoxybate, and tested these formulations in dogs alongside an immediaterelease formulation to compare the relative pharmacokinetics (PK) ofthese formulations. The results of Liang's testing are reported below:

Mean GHB Concentrations (ug/mL) Period 1 2 3 4 Time Point (Hr) DR1-w/Acid DR1-No Acid IR DR2 0 0.00 0.00 0.00 0.00 0.5 0.00 0.00 116.04 0.001 0.00 4.76 248.27 1.53 2 4.99 11.62 195.51 32.52 3 26.31 31.88 117.56100.99 4 35.14 38.26 47.21 100.57 5 29.18 34.77 8.74 54.99 6 21.09 27.830.00 23.42 7 11.25 9.13 0.00 7.52 8 8.67 2.53 0.00 0.34 10 1.43 3.030.00 0.00 12 0.98 0.67 0.00 0.00 14 0.43 0.00 0.00 0.00 Tmax (Hr) 4.25.2 1.2 3.7 Cmax (ug/mL) 38.77 58.44 249.5 112.7 AUClast 134.3 162.6601.0 318.4 Rel BA 22% 27% 100% 53% DR1-w/ Acid: Two 1 g DR capsulesadministered at time zero DR1-No Acid: Two 1 g DR capsules administeredat time zero IR: Two 1 g IR capsules administered at time zero DR2: Two1 g DR capsules administered at time zero

As can be seen, by encapsulating the sodium oxybate in anenteric/delayed release coating, Liang decreased the AUC of the sodiumoxybate significantly. One of the formulations, DR1-w/Acid, had arelative bioavailability of only 22% compared to the immediate releasedosage form. DR2 had the greatest relative bioavailability, but stillonly 53% compared to the immediate release dosage form. One can easilycalculate that any of the envisioned combinations of immediate release(IR) components and delayed release (DR) components as described in col.5 lines 3 to 28 of U.S. Pat. No. 8,193,211 will not give a relativebioavailability greater than 78%.

All of these formulations are inconvenient for at least two reasons: (1)the low relative bioavailability necessitates an increase in the dosecompared to current IR treatments which already require a large dose(4.5 to 9 g a day), and (2) when provided in the form of pills, apatient must swallow around 4 to 9 pills per dose, which is a seriousinconvenience for the patient and potential drawback for patientcompliance.

Various other techniques are known for formulating modified releasedosage forms including, for example, the techniques described in U.S.Pat. No. 8,101,209 to Legrand et al. (“Legrand”). Legrand provides asystem ensuring that the active ingredient is released with certaintyfrom the modified release dosage form by means of a dual mechanism of“time-dependent” and “pH-dependent” release. Legrand did not describeany dosage forms for delivering sodium oxybate or other forms ofgamma-hydroxybutyrate.

Another drawback of Xyrem® is the high level of the daily dose,generally 7.5 g or 9 g of sodium oxybate taken daily over long periodsof time. This represents a very high sodium intake which is notrecommended in persons with high blood pressure, risk of cardiovasculardisease, stroke or coronary heart disease (See WHO. Guideline: Sodiumintake for adults and children. Geneva, World Health Organization (WHO),2012.).

Accordingly, one object of the present invention is to provide modifiedrelease formulations of gamma-hydroxybutyrate that are administered onlyonce at bed-time with improved dissolution and pharmacokinetic profiles.

Another object of the present invention is to provide modified releaseformulations of gamma-hydroxybutyrate that optimize the bioavailabilityof the gamma-hydroxybutyrate, and roughly approximate thebioavailability of an equal dose of an immediate release liquid solutionof sodium oxybate administered twice nightly.

Still another object of the present invention is to provide once-nightlymodified release formulations of gamma-hydroxybutyrate that roughlyapproximate or exceed the bioavailability of an equal dose of animmediate release solution of sodium oxybate administered twice nightly,across the entire therapeutic range of sodium oxybate doses.

Yet another object of the present invention is to provide modifiedrelease formulations of gamma-hydroxybutyrate which, 8 hours afteradministration, produce very little residual drug content in thebloodstream of most patients but still similar to the one observed afteradministration of an equal dose of an immediate release liquid solutionof sodium oxybate administered twice nightly.

Yet another object of the present invention is to improve thetherapeutic effectiveness and safety profile of gamma-hydroxybutyratebased on novel dissolution and pharmacokinetic profiles.

Yet another object of the present invention is to provide modifiedrelease formulations of gamma-hydroxybutyrate that yield a similarpharmacokinetic profile compared to an immediate release liquid solutionof sodium oxybate administered twice nightly while potentially giving areduced dose.

Yet another object of the present invention is to provide modifiedrelease formulations of gamma-hydroxybutyrate that allow once dailyadministration and reduced dose compared to the commercial treatmentXyrem®.

Yet another object of the present invention is to provide a convenientdosage form of gamma-hydroxybutyrate that can be easily swallowed.

Yet another object of the present invention is to provide modifiedrelease formulations of gamma-hydroxybutyrate that are administered onlyonce at bed-time with improved dissolution and pharmacokinetic profilesand reduced sodium content compared to an immediate release liquidsolution of sodium oxybate administered twice nightly.

SUMMARY OF INVENTION

As the prior art demonstrates, it is extremely difficult to find amodified release formulation of gamma-hydroxybutyrate which, whenadministered only once nightly, has a comparable bioavailability to animmediate release liquid solution of sodium oxybate administered twicenightly. Even if such a formulation could be found, it probably stillwould not be satisfactory because the dose of gamma-hydroxybutyratediffers among individuals, and the size of the dose affects the amountof drug absorbed through the GI tract. I.e., even if the prior artformulations achieved comparable bioavailability at one dose—which theydo not—they would not be comparable at other doses.

The inventors have discovered a novel relationship between the in vitrorelease profile of gamma-hydroxybutyrate modified release formulationsand in vivo absorption which permits, for the first time, a modifiedrelease formulation of gamma-hydroxybutyrate that approximates thebioavailability of a twice-nightly equipotent immediate release liquidsolution of sodium oxybate, and that does so across a range oftherapeutic doses. In particular, the inventors have discovered that amodified release formulation of gamma-hydroxybutyrate that rapidlyreleases half of its gamma-hydroxybutyrate in 0.1N hydrochloric aciddissolution medium, and rapidly releases the other half of itsgamma-hydroxybutyrate in phosphate buffer pH 6.8 dissolution medium,approximates or exceeds the in vivo bioavailability of an equipotentimmediate release liquid solution of sodium oxybate administered twicenightly. This can be seen by comparing the formulations of Examples 1and 4, which satisfy the dissolution requirements of the presentinvention and achieve the necessary bioavailability for a commercialformulation, with the Comparative formulation of Example 7, whichexhibited a dissolution profile similar to prior art dissolutionprofiles, and did not achieve the necessary bioavailability for acommercial formulation.

This phenomenon is observed especially with higher doses ofgamma-hydroxybutyrate. For example, the inventors have discovered that amodified release composition of gamma-hydroxybutyrate according to theinvention administered once approximately two hours after a standardizedevening meal at the dose equivalent to 7.5 g of sodium oxybate resultsin a similar pharmacokinetic profile as an immediate release liquidsolution of sodium oxybate given in two separate equal doses of 4.5 g ofsodium oxybate each administered at t₀ and t_(4h).

The modified release formulations of gamma-hydroxybutyrate preferablyhave both immediate release and modified release portions. The releaseof gamma-hydroxybutyrate from the immediate release portion ispractically uninhibited, and occurs almost immediately in 0.1Nhydrochloric acid dissolution medium. In contrast, while the modifiedrelease portion also preferably releases its gamma-hydroxybutyratealmost immediately when fully triggered, the release is not triggereduntil a predetermined lag-time or the drug is subjected to a suitabledissolution medium such as a phosphate buffer pH 6.8 dissolution medium.Without wishing to be bound by any theory, it is believed that thisrapid release in two dissolution media compresses the bloodconcentration vs. time curve in vivo, resulting in a relativebioavailability of gamma-hydroxybutyrate comparable to or greater thanan equipotent dose of an immediate-release liquid solution of sodiumoxybate administered twice nightly.

Formulations that achieve this improved bioavailability can be describedusing several different pharmacokinetic and in vitro dissolutionparameters. In a first principal embodiment, the invention provides amodified release formulation of gamma-hydroxybutyrate, preferablycomprising immediate release and modified release portions, wherein a7.5 g dose of the formulation has been shown to achieve a mean AUC_(inf)of greater than 340 hr×microgram/mL.

In a second principal embodiment, the invention provides a modifiedrelease formulation of gamma-hydroxybutyrate, preferably comprisingimmediate release and modified release portions, wherein a 7.5 g dose ofthe formulation has been shown to achieve a mean AUC_(inf) of greaterthan 340 hr×microgram/mL, and a mean C_(8h) that is from 50% to 130% ofthe mean C_(8h) provided by an equal dose of an immediate release liquidsolution of sodium oxybate administered at t₀ and t_(4h) in equallydivided doses approximately two hours after a standardized evening meal.

In a third principal embodiment, the invention provides a modifiedrelease formulation of gamma-hydroxybutyrate, preferably comprisingimmediate release and modified release portions, wherein the formulationreleases (a) at least 80% of its gamma-hydroxybutyrate at 3 hours whentested in a dissolution apparatus 2 according to USP 38 <711> in 900 mLof 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of37° C. and a paddle speed of 75 rpm, and (b) from 10% to 65%, of itsgamma-hydroxybutyrate at one hour and three hours when tested in adissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1Nhydrochloric acid at a temperature of 37° C. and a paddle speed of 75rpm.

In a fourth principal embodiment, the invention provides a modifiedrelease formulation of gamma-hydroxybutyrate, comprising immediaterelease and modified release portions, wherein (a) the formulationreleases at least 80% of its gamma-hydroxybutyrate at 3 hours, whentested in a dissolution apparatus 2 according to USP 38 <711> in 900 mLof 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of37° C. and a paddle speed of 75 rpm, (b) the formulation releases from10% to 65%, of its gamma-hydroxybutyrate at one hour and three hourswhen tested in a dissolution apparatus 2 according to USP 38 <711> in900 mL of 0.1N hydrochloric acid at a temperature of 37° C. and a paddlespeed of 75 rpm, and (c) the modified release portion releases greaterthan 80% of its gamma-hydroxybutyrate at 3 hours in a dissolution teststarted in 750 mL of 0.1N hydrochloric acid for 2 hours then switched to950 mL 0.05M monobasic potassium phosphate buffer adjusted to pH 6.8 ata temperature of 37° C. and a paddle speed of 75 rpm.

In a fifth principal embodiment, the invention provides a modifiedrelease formulation of gamma-hydroxybutyrate, comprising immediaterelease and modified release portions, wherein (a) the formulationreleases at least 80% of its gamma-hydroxybutyrate at 3 hours, whentested in a dissolution apparatus 2 according to USP 38 <711> in 900 mLof 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of37° C. and a paddle speed of 75 rpm, (b) the formulation releases 10% to65%, of its gamma-hydroxybutyrate at one hour and at three hours whentested in a dissolution apparatus 2 according to USP 38 <711> in 900 mLof 0.1N hydrochloric acid at a temperature of 37° C. and a paddle speedof 75 rpm, (c) the formulation releases greater than 60% of itsgamma-hydroxybutyrate at 10 hours when tested in a dissolution apparatus2 according to USP 38 <711> in 900 mL of 0.1N hydrochloric acid at atemperature of 37° C. and a paddle speed of 75 rpm, and (d) the modifiedrelease portion releases greater than 80% of its gamma-hydroxybutyrateat 3 hours in a dissolution test started in 750 mL of 0.1N hydrochloricacid for 2 hours then switched to 950 mL 0.05M monobasic potassiumphosphate buffer adjusted to pH 6.8 at a temperature of 37° C. and apaddle speed of 75 rpm.

In a sixth principal embodiment, the invention provides a modifiedrelease formulation of gamma-hydroxybutyrate, comprising immediaterelease and modified release portions, wherein (a) a 7.5 g dose of theformulation has been shown to achieve a mean AUC_(inf) of greater than340 hr×microgram/mL, and a mean C_(8h) that is from 50% to 130%, of themean C_(8h) provided by an equal dose of an immediate release liquidsolution of sodium oxybate administered at t₀ and t_(4h) in equallydivided doses approximately two hours after a standardized evening meal,and (b) the formulation releases (i) at least 80% or 90% of itsgamma-hydroxybutyrate at 3 hours when tested in a dissolution apparatus2 according to USP 38 <711> in 900 mL of 0.05M monobasic potassiumphosphate buffer pH 6.8 at a temperature of 37° C. and a paddle speed of75 rpm, and (ii) from 10% to 65%, of its gamma-hydroxybutyrate at onehour and three hours when tested in a dissolution apparatus 2 accordingto USP 38 <711> in 900 mL of 0.1N hydrochloric acid at a temperature of37° C. and a paddle speed of 75 rpm, and (c) the modified releaseportion releases greater than 80% of its gamma-hydroxybutyrate at 3hours in a dissolution test started in 750 mL of 0.1N hydrochloric acidfor 2 hours then switched to 950 mL 0.05M monobasic potassium phosphatebuffer adjusted to pH 6.8 at a temperature of 37° C. and a paddle speedof 75 rpm.

In a seventh principal embodiment, the invention provides a modifiedrelease formulation of gamma-hydroxybutyrate comprising immediaterelease and modified release portions, wherein: (a) said immediaterelease portion releases greater than 80% of its gamma-hydroxybutyrateat one hour when tested in a dissolution apparatus 2 according to USP 38<711> in 900 mL of 0.1N hydrochloric acid at a temperature of 37° C. anda paddle speed of 75 rpm; (b) said modified release portion releasesless than 20% of its gamma-hydroxybutyrate at one hour when tested in adissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1Nhydrochloric acid at a temperature of 37° C. and a paddle speed of 75rpm; and (c) said modified release portion releases greater than 80% ofits gamma-hydroxybutyrate at three hours when tested in a dissolutionapparatus 2 according to USP 38 <711> in 900 mL of 0.05M monobasicpotassium phosphate buffer pH 6.8 at a temperature of 37° C. and apaddle speed of 75 rpm.

In an eighth principal embodiment, the invention provides a modifiedrelease formulation of gamma-hydroxybutyrate comprising immediaterelease and modified release portions, wherein: (a) said immediaterelease portion releases greater than 80% of its gamma-hydroxybutyrateat one hour when tested in a dissolution apparatus 2 according to USP 38<711> in 900 mL of 0.1N hydrochloric acid at a temperature of 37° C. anda paddle speed of 75 rpm; (b) said modified release portion releasesless than 20% of its gamma-hydroxybutyrate at one hour when tested in adissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1Nhydrochloric acid at a temperature of 37° C. and a paddle speed of 75rpm; (c) said modified release portion releases greater than 80% of itsgamma-hydroxybutyrate at three hours when tested in a dissolutionapparatus 2 according to USP 38 <711> in 900 mL of 0.05M monobasicpotassium phosphate buffer pH 6.8 at a temperature of 37° C. and apaddle speed of 75 rpm; and (d) said modified release portion releasesgreater than 80% of its gamma-hydroxybutyrate at 3 hours in adissolution test started in 750 mL of 0.1N hydrochloric acid for 2 hoursthen switched to 950 mL 0.05M monobasic potassium phosphate bufferadjusted to pH 6.8 at a temperature of 37° C. and a paddle speed of 75rpm.

In a ninth principal embodiment, the invention provides a modifiedrelease formulation of gamma-hydroxybutyrate, preferably comprisingimmediate release and modified release portions, wherein 4.5 g, 6 g, 7.5g, and 9 g doses of the formulation have been shown to achieve arelative bioavailability (RBA) of greater than 80% when compared to anequal dose of an immediate release liquid solution of sodium oxybateadministered at t₀ and t_(4h) in equally divided doses, whenadministered approximately two hours after a standardized evening meal.

In a tenth principal embodiment, the invention provides a modifiedrelease formulation of gamma-hydroxybutyrate, preferably comprisingimmediate release and modified release portions, wherein 4.5 g and 9 gdoses of the formulation have been shown to achieve a relativebioavailability (RBA) of greater than 80% when compared to an equal doseof an immediate release liquid solution of sodium oxybate administeredat t₀ and t_(4h) in equally divided doses, when administeredapproximately two hours after a standardized evening meal.

In an eleventh principal embodiment, the invention provides a modifiedrelease formulation of gamma-hydroxybutyrate, preferably comprisingimmediate release and modified release portions, that yields a plasmaconcentration versus time curve when administered once nightly at astrength of 4.5 g, 6.0 g or 7.5 g approximately two hours after astandardized evening meal substantially as depicted in FIG. 12 or FIG.13 for the corresponding strength.

In a twelfth principal embodiment, the invention provides a modifiedrelease formulation of gamma-hydroxybutyrate, preferably comprisingimmediate release and modified release portions, that yields a plasmaconcentration versus time curve when administered once nightly at astrength of 4.5 g approximately two hours after a standardized eveningmeal substantially as depicted in FIG. 22.

In a thirteenth principal embodiment, the invention provides a modifiedrelease formulation of gamma-hydroxybutyrate, preferably comprisingimmediate release and modified release portions, that yields adissolution profile substantially as depicted in FIG. 7 and FIG. 8.

In a fourteenth principal embodiment, the invention provides a modifiedrelease formulation of gamma-hydroxybutyrate, preferably comprisingimmediate release and modified release portions, that yields adissolution profile substantially as depicted in FIG. 20 and FIG. 21.

In a fifteenth principal embodiment, the invention provides a modifiedrelease formulation of gamma-hydroxybutyrate comprising immediaterelease and modified release portions, wherein said modified releaseportion yields a dissolution profile substantially as depicted in FIG. 3or FIG. 16.

In a sixteenth principal embodiment, the invention provides a modifiedrelease formulation of gamma-hydroxybutyrate, comprising immediaterelease and modified release portions that yields a dissolution profilebetween the minimum and maximum values depicted in FIG. 25 and FIG. 26.

In a seventeenth principal embodiment, the invention provides a modifiedrelease formulation of gamma-hydroxybutyrate, comprising immediaterelease and modified release portions that yields a dissolution profilebetween the minimum and maximum values depicted in FIG. 27 and FIG. 28.

In an eighteenth principal embodiment, the invention provides a modifiedrelease formulation of gamma-hydroxybutyrate yielding a dissolutionprofile substantially as shown in any one of FIGS. 29 through 89.

A nineteenth principal embodiment of the present invention provides amodified release formulation of gamma-hydroxybutyrate, preferablycomprising immediate release and modified release portions, that yieldsa plasma concentration versus time curve when administered once nightlyat a strength of 4.5 g, 7.5 g or 9.0 g approximately two hours after astandardized evening meal substantially as depicted in FIG. 90 for thecorresponding strength.

A twentieth principal embodiment of the present invention provides amodified release formulation of gamma-hydroxybutyrate, preferablycomprising immediate release and modified release portions that yields adissolution profile between the minimum and maximum values depicted inFIG. 26 and FIG. 28.

Still further embodiments relate to methods of using the formulations ofthe present invention to treat narcolepsy and associated disorders andsymptoms, and to physical aspects of the formulations of the presentinvention. Additional principal embodiments and sub-embodiments theretowill be set forth in part in the description which follows, and in partwill be obvious from the description, or may be learned by practice ofthe invention. The embodiments and advantages of the invention will berealized and attained by means of the elements and combinationsparticularly pointed out in the appended claims. It is to be understoodthat both the foregoing general description and the following detaileddescription are exemplary and explanatory only and are not restrictiveof the invention, as claimed.

DESCRIPTION OF THE FIGURES

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application publication withcolor drawing(s) will be provided by the Office upon request and paymentof the necessary fee.

FIG. 1 depicts the qualitative and quantitative structure of theimmediate release (IR) and modified release (MR) microparticles ofgamma-hydroxybutyrate of Example 1.

FIG. 2 plots a time release dissolution profile of IR microparticles ofgamma-hydroxybutyrate of Example 1 (♦) and 1bis (▪) in a 0.1N HCldissolution medium.

FIG. 3 plots a time release dissolution profile of MR microparticles ofgamma-hydroxybutyrate of Example 1 in two sequential dissolution media(0.1 N HCl/phosphate buffer pH 6.8).

FIG. 4 plots a time release dissolution profile of MR microparticles (▴symbols) of Example 1 in two sequential dissolution media (0.1 NHCl/phosphate buffer pH 6.8), overlaid against dissolution profiledescribed in FIG. 3 of U.S. Pat. No. 8,193,211 (● symbols).

FIG. 5 plots a time release dissolution profile of the finishedformulation of Example 1 in deionized water.

FIG. 6 plots a time release dissolution profile of the finishedcomposition of Example 1 in deionized water (▴ symbols), overlaidagainst dissolution profile described in FIG. 2 of USP 2012/0076865 (●symbols).

FIG. 7 plots time release dissolution profiles in 0.1N HCl of fourseparate batches of finished compositions produced in accordance withExample 1 or Example 1bis.

FIG. 8 plots time release dissolution profiles in phosphate buffer pH6.8 of four separate batches of finished compositions produced inaccordance with Example 1 or Example 1bis.

FIG. 9 plots time release dissolution profiles in 0.1N HCl of MRmicroparticles of gamma-hydroxybutyrate produced in accordance withExample 1 at 75 rpm (▪ symbols) and 100 rpm (▴ symbols).

FIG. 10 plots time release dissolution profiles in 0.1N HCl of finishedcomposition produced in accordance with Example 1 performed with paddlerotation speed set at 75 rpm (▪ symbols) and 100 rpm (▴ symbols).

FIG. 11 plots the mean+SD (standard deviation) plasmagamma-hydroxybutyrate concentrations (microgram/mL) versus time for twodifferent modified release formulations of gamma-hydroxybutyrate testedin vivo according to the methods of Example 3. Time profiles are givenfor a 4.5 g dose of the finished composition of Example 1bisadministered once (● symbols) (N=26) and a 4.5 g dose of Xyrem®administered in two divided doses (− symbols) (N=15).

FIG. 12 plots the mean+SD (standard deviation) plasmagamma-hydroxybutyrate concentrations (microgram/mL) versus time after aSingle Oral Administration of 4.5 g (● symbols) and 6 g (▴ symbols) offinished composition of Example 1bis in the same 7 subjects tested invivo according to the methods of Example 3.

FIG. 13 plots the mean+SD (standard deviation) plasmagamma-hydroxybutyrate concentrations (microgram/mL) versus time of threeseparate doses of finished composition prepared according to Example1bis tested in vivo according to the methods of Example 3. Mean timeprofiles are given for a single oral administration of 4.5 g (N=26) (●),6.0 g (N=19) (▴) or 7.5 g (▪) doses (N=11).

FIG. 14 plots the mean plasma gamma-hydroxybutyrate Concentrations(microgram/mL) of a Single dose of 7.5 g (▪) of finished compositionprepared according to Example 1bis compared to 2×4.5 g Xyrem® post-fed(Source NDA 21-196 review).

FIG. 15 depicts the qualitative and quantitative structure of theimmediate release (IR) and modified release (MR) microparticles ofgamma-hydroxybutyrate of Example 4.

FIG. 16 plots a time release dissolution profile of MR microparticles ofgamma-hydroxybutyrate of Example 4 in two sequential dissolution media(0.1 N HCl and phosphate buffer pH 6.8).

FIG. 17 plots a time release dissolution profile of MR microparticles (▴symbols) of Example 4 in two sequential dissolution media (0.1 N HCl andphosphate buffer pH 6.8), overlaid against dissolution profile describedin FIG. 3 of U.S. Pat. No. 8,193,211 (● symbols).

FIG. 18 plots a time release dissolution profile of the finishedcomposition of Example 4 in deionized water.

FIG. 19 plots a time release dissolution profile of the finishedcomposition of Example 4 in deionized water (● symbols), overlaidagainst dissolution profile described in FIG. 2 of USP 2012/0076865 (▴symbols).

FIG. 20 plots time release dissolution profiles in 0.1N HCl of threeseparate batches of finished compositions produced in accordance withExample 4 or 4bis.

FIG. 21 plots a time release dissolution profile in phosphate buffer pH6.8 of a finished composition produced in accordance with Example 4.

FIG. 22 plots mean plasma gamma-hydroxybutyrate concentration(microgram/mL) time profiles after a Single Dose of 4.5 g (▪) offinished composition of Example 4bis, N=15 compared to 2×2.25 g Xyrem®post fed, N=15.

FIG. 23 depicts the qualitative and quantitative structure of theimmediate release (IR) and modified release (MR) microparticles ofgamma-hydroxybutyrate of Example 7.

FIG. 24 plots a time release dissolution profile of MR microparticles ofgamma-hydroxybutyrate of Example 7 (▴ symbols) in two sequentialdissolution media (0.1 N HCl and phosphate buffer pH 6.8), overlaidagainst dissolution profile described in FIG. 3 of U.S. Pat. No.8,193,211 (● symbols).

FIG. 25 plots the Min (▪) and Max (▴) values of a preferred dissolutionprofile in 0.1N HCl of finished composition according to the invention.

FIG. 26 plots the Min (▪) and Max (▴) values of a preferred dissolutionprofile in phosphate buffer pH 6.8 of finished composition according tothe invention.

FIG. 27 plots the Min (▪) and Max (▴) values of another preferreddissolution profile in phosphate buffer pH 6.8 of finished compositionaccording to the invention.

FIG. 28 plots the Min (▪) and Max (▴) values of another preferreddissolution profile in 0.1N HCl of finished composition according to theinvention.

FIG. 29 depicts a dissolution profile determined in 0.1N HCl using a USPapparatus 2 for the formulation of Example 9.1 5 minutes and 15 minutesafter reconstitution in water.

FIG. 30 depicts a dissolution profile determined in 0.1N HCl using a USPapparatus 2 for the formulation of Example 9.2 5 minutes and 15 minutesafter reconstitution in water.

FIG. 31 depicts a dissolution profile determined in 0.1N HCl using a USPapparatus 2 for the formulation of Example 9.3 5 minutes and 15 minutesafter reconstitution in water.

FIG. 32 depicts the dissolution profile determined in 0.1N HCl using aUSP apparatus 2 of a 9 g dose of the formulation of Example 10 with andwithout rinsing.

FIG. 33 depicts the dissolution profile of the MR portion of theformulation of Example 11a in 900 ml of 0.1N HCl and pH 6.8 phosphatebuffer (0.05M monobasic potassium phosphate solution—pH adjusted to 6.8with 5N NaOH) using a USP apparatus 2.

FIG. 34 depicts the dissolution profile of the formulation of Example11a in 900 ml of 0.1N HCl using a USP apparatus 2.

FIG. 35 depicts the dissolution profile of the formulation of Example11a in pH6.8 phosphate buffer (0.05M monobasic potassium phosphatesolution—pH adjusted to 6.8 with 5N NaOH) using a USP apparatus 2.

FIG. 36 depicts the dissolution profile of the MR portion of theformulation of Example 11b in 900 ml of 0.1N HCl using a USP apparatus2.

FIG. 37 depicts the dissolution profile of the formulation of Example11b in 900 ml of 0.1N HCl using a USP apparatus 2.

FIG. 38 depicts the dissolution profile of the formulation of Example11b in pH6.8 phosphate buffer (0.05M monobasic potassium phosphatesolution—pH adjusted to 6.8 with 5N NaOH) using a USP apparatus 2.

FIG. 39 depicts the dissolution profile of the formulation of Example11c in 900 ml of 0.1N HCl using a USP apparatus 2.

FIG. 40 depicts the dissolution profile of the formulation of Example11c in pH6.8 phosphate buffer (0.05M monobasic potassium phosphatesolution—pH adjusted to 6.8 with 5N NaOH) using a USP apparatus 2.

FIG. 41 depicts the dissolution profile of the MR portion of theformulation of Example 12a in 900 ml of 0.1N HCl using a USP apparatus2.

FIG. 42 depicts the dissolution profile of the formulation of Example12a using a USP apparatus 2 in 0.1N HCl.

FIG. 43 depicts the dissolution profile of the formulation of Example12b in 900 ml of 0.1N HCl using a USP apparatus 2.

FIG. 44 depicts the dissolution profile of the formulation of Example12b in pH6.8 phosphate buffer (0.05M monobasic potassium phosphatesolution—pH adjusted to 6.8 with 5N NaOH) using a USP apparatus 2.

FIG. 45 depicts the dissolution profile of the MR portion of theformulation of Example 13 in 900 ml of 0.1N HCl and pH 6.8 phosphatebuffer (0.05M monobasic potassium phosphate solution—pH adjusted to 6.8with 5N NaOH) using a USP apparatus 2.

FIG. 46 depicts the dissolution profile of the formulation of Example 13in 900 ml of 0.1N HCl using a USP apparatus 2.

FIG. 47 depicts the dissolution profile of the formulation of Example 13in pH6.8 phosphate buffer (0.05M monobasic potassium phosphatesolution—pH adjusted to 6.8 with 5N NaOH) using a USP apparatus 2.

FIG. 48 depicts the dissolution profile of the MR portion of theformulation of Example 14 in 900 ml of 0.1N HCl and pH 6.8 phosphatebuffer (0.05M monobasic potassium phosphate solution—pH adjusted to 6.8with 5N NaOH) using a USP apparatus 2.

FIG. 49 depicts the dissolution profile of the formulation of Example 14in 900 ml of 0.1N HCl using a USP apparatus 2.

FIG. 50 depicts the dissolution profile of the formulation of Example 14in pH6.8 phosphate buffer (0.05M monobasic potassium phosphatesolution—pH adjusted to 6.8 with 5N NaOH) using a USP apparatus 2.

FIG. 51 depicts the dissolution profile of the MR portion of theformulation of Example 15a (coating weight 35%) in 900 ml of 0.1N HClusing a USP apparatus 2.

FIG. 52 depicts the dissolution profile of the MR portion of theformulation of Example 15a (coating weight 50%) in 900 ml of 0.1N HClusing a USP apparatus 2.

FIG. 53 depicts the dissolution profile of the formulation of Example15a in 900 ml of 0.1N HCl using a USP apparatus 2.

FIG. 54 depicts the dissolution profile of the MR portion of theformulation of Example 15b in 900 ml of 0.1N HCl and pH 6.8 phosphatebuffer (0.05M monobasic potassium phosphate solution—pH adjusted to 6.8with 5N NaOH) using a USP apparatus 2.

FIG. 55 depicts the dissolution profile of the formulation of Example15b in 900 ml of 0.1N HCl using a USP apparatus 2.

FIG. 56 depicts the dissolution profile of the formulation of Example15b in pH6.8 phosphate buffer (0.05M monobasic potassium phosphatesolution—pH adjusted to 6.8 with 5N NaOH) using a USP apparatus 2.

FIG. 57 depicts the dissolution profile of the MR portion of theformulation of Example 15c in 900 ml of 0.1N HCl using a USP apparatus2.

FIG. 58 depicts the dissolution profile of the formulation of Example15c in 900 ml of 0.1N HCl using a USP apparatus 2.

FIG. 59 depicts the dissolution profile of the formulation of Example15c in pH6.8 phosphate buffer (0.05M monobasic potassium phosphatesolution—pH adjusted to 6.8 with 5N NaOH) using a USP apparatus 2.

FIG. 60 depicts the dissolution profile of the MR portion of theformulation of Example 15d in 900 ml of 0.1N HCl and pH 6.8 phosphatebuffer (0.05M monobasic potassium phosphate solution—pH adjusted to 6.8with 5N NaOH) using a USP apparatus 2.

FIG. 61 depicts the dissolution profile of the formulation of Example15d in 900 ml of 0.1N HCl using a USP apparatus 2.

FIG. 62 depicts the dissolution profile of the formulation of Example15d in pH6.8 phosphate buffer (0.05M monobasic potassium phosphatesolution—pH adjusted to 6.8 with 5N NaOH) using a USP apparatus 2.

FIG. 63 depicts the dissolution profile of the MR portion of theformulation of Example 16a in 900 ml of 0.1N HCl and pH 6.8 phosphatebuffer (0.05M monobasic potassium phosphate solution—pH adjusted to 6.8with 5N NaOH) using a USP apparatus 2.

FIG. 64 depicts the dissolution profile of the formulation of Example16a in 900 ml of 0.1N HCl using a USP apparatus 2.

FIG. 65 depicts the dissolution profile of the formulation of Example16a in pH6.8 phosphate buffer (0.05M monobasic potassium phosphatesolution—pH adjusted to 6.8 with 5N NaOH) using a USP apparatus 2.

FIG. 66 depicts the dissolution profile of the MR portion of theformulation of Example 16b in 900 ml of 0.1N HCl and pH 6.8 phosphatebuffer (0.05M monobasic potassium phosphate solution—pH adjusted to 6.8with 5N NaOH) using a USP apparatus 2.

FIG. 67 depicts the dissolution profile of the formulation of Example16b in 900 ml of 0.1N HCl using a USP apparatus 2.

FIG. 68 depicts the dissolution profile of the formulation of Example16b in pH6.8 phosphate buffer (0.05M monobasic potassium phosphatesolution—pH adjusted to 6.8 with 5N NaOH) using a USP apparatus 2.

FIG. 69 depicts the dissolution profile of the MR portion of theformulation of Example 16c in 900 ml of 0.1N HCl and pH 6.8 phosphatebuffer (0.05M monobasic potassium phosphate solution—pH adjusted to 6.8with 5N NaOH) using a USP apparatus 2.

FIG. 70 depicts the dissolution profile of the formulation of Example16c in 900 ml of 0.1N HCl using a USP apparatus 2.

FIG. 71 depicts the dissolution profile of the formulation of Example16c in pH6.8 phosphate buffer (0.05M monobasic potassium phosphatesolution—pH adjusted to 6.8 with 5N NaOH) using a USP apparatus 2.

FIG. 72 depicts the dissolution profile of the MR portion of theformulation of Example 16d in 900 ml of 0.1N HCl using a USP apparatus2.

FIG. 73 depicts the dissolution profile of the MR portion of theformulation of Example 17a in 900 ml of 0.1N HCl using a USP apparatus2.

FIG. 74 depicts the dissolution profile of the formulation of Example17a in 900 ml of 0.1N HCl using a USP apparatus 2.

FIG. 75 depicts the dissolution profile of the formulation of Example17a in pH6.8 phosphate buffer (0.05M monobasic potassium phosphatesolution—pH adjusted to 6.8 with 5N NaOH) using a USP apparatus 2.

FIG. 76 depicts the dissolution profile of the MR portion of theformulation of Example 17b in 900 ml of 0.1N HCl and pH 6.8 phosphatebuffer (0.05M monobasic potassium phosphate solution—pH adjusted to 6.8with 5N NaOH) using a USP apparatus 2.

FIG. 77 depicts the dissolution profile of the formulation of Example17b in 900 ml of 0.1N HCl using a USP apparatus 2.

FIG. 78 depicts the dissolution profile of the formulation of Example17b in pH6.8 phosphate buffer (0.05M monobasic potassium phosphatesolution—pH adjusted to 6.8 with 5N NaOH) using a USP apparatus 2.

FIG. 79 depicts the dissolution profile of the MR portion of theformulation of Example 17c in 900 ml of 0.1N HCl and pH 6.8 phosphatebuffer (0.05M monobasic potassium phosphate solution—pH adjusted to 6.8with 5N NaOH) using a USP apparatus 2.

FIG. 80 depicts the dissolution profile of the formulation of Example17c in 900 ml of 0.1N HCl using a USP apparatus 2.

FIG. 81 depicts the dissolution profile of the formulation of Example17c in pH6.8 phosphate buffer (0.05M monobasic potassium phosphatesolution—pH adjusted to 6.8 with 5N NaOH) using a USP apparatus 2.

FIG. 82 depicts a preferred dissolution profile of sodium oxybate MRmicroparticles in 900 ml 0.1N HCl using a USP apparatus 2 at 75 rpm.

FIG. 83 depicts a preferred dissolution profile of sodium oxybate MRmicroparticles in 900 ml pH 6.8 phosphate buffer (0.05M monobasicpotassium phosphate solution—pH adjusted to 6.8 with 5N NaOH) using aUSP apparatus 2 at 75 rpm.

FIG. 84 depicts a preferred dissolution profile of a sodium oxybatefinished formulation comprising IR and MR microparticles in 900 ml 0.1NHCl using a USP apparatus 2 at 75 rpm.

FIG. 85 depicts a preferred dissolution profile of a sodium oxybatefinished formulation comprising IR and MR microparticles in 900 ml pH6.8 phosphate buffer (0.05M monobasic potassium phosphate solution—pHadjusted to 6.8 with 5N NaOH) using a USP apparatus 2 at 75 rpm.

FIG. 86 is a dissolution profile in 0.1N HCl of two separate batches ofthe sodium oxybate MR microparticles present in the finished compositionof Example 18.

FIG. 87 is a dissolution profile in phosphate buffer pH 6.8 of twoseparate batches of the sodium oxybate MR microparticles present in thefinished composition of Example 18.

FIG. 88 is a dissolution profile in 0.1N HCl of two unit doses of 3 g (▴symbols) and 4.5 g (● symbols) of the finished composition of Example18.

FIG. 89 is a dissolution profile in phosphate buffer pH 6.8 of two unitdoses of 3 g (▴ symbols) and 4.5 g (● symbols) of the finishedcomposition of Example 18.

FIG. 90 plots mean plasma gamma-hydroxybutyrate concentrations(microgram/mL)+SD—time profiles after a single oral administration of4.5 g (● symbols), 7.5 g (▪ symbols) and 9 g (▴ symbols) of the finishedcomposition of Example 18.

DETAILED DESCRIPTION OF THE INVENTION

The present invention may be understood more readily by reference to thefollowing detailed description of preferred embodiments of the inventionand the Examples included therein.

Definitions and Use of Terms

Wherever an analysis or test is required to understand a given propertyor characteristic recited herein, it will be understood that theanalysis or test is performed in accordance with applicable guidances,draft guidances, regulations and monographs of the United States Foodand Drug Administration (“FDA”) and United States Pharmacopoeia (“USP”)applicable to drug products in the United States in force as of Nov. 1,2015 unless otherwise specified. Clinical endpoints can be judged withreference to standards adopted by the American Academy of SleepMedicine, including standards published at C Iber, S Ancoli-Israel, AChesson, SF Quan. The AASM Manual for the Scoring of Sleep andAssociated Events. Westchester, Ill.: American Academy of SleepMedicine; 2007.

When a pharmacokinetic comparison is made between a formulationdescribed or claimed herein and a reference product, it will beunderstood that the comparison is preferably performed in a suitabledesigned cross-over trial, although it will also be understood that across-over trial is not required unless specifically stated. It willalso be understood that the comparison can be made either directly orindirectly. For example, even if a formulation has not been testeddirectly against a reference formulation, it can still satisfy acomparison to the reference formulation if it has been tested against adifferent formulation, and the comparison with the reference formulationcan be deduced therefrom.

As used in this specification and in the claims which follow, thesingular forms “a,” “an” and “the” include plural referents unless thecontext dictates otherwise. Thus, for example, reference to “aningredient” includes mixtures of ingredients, reference to “an activepharmaceutical agent” includes more than one active pharmaceuticalagent, and the like.

“Bioavailability” means the rate and extent to which the activeingredient or active moiety is absorbed from a drug product and becomesavailable at the site of action.

“Relative bioavailability” or “Rel BA” or “RBA” means the percentage ofmean AUC_(inf) of the tested product relative to the mean AUC_(inf) ofthe reference product. Unless otherwise specified, relativebioavailability refers to the percentage of the mean AUC_(inf) observedfor a full dose of the test product relative to the mean AUC_(inf)observed for two ½-doses of an immediate release liquid solutionadministered four hours apart.

“Bioequivalence” means the absence of a significant difference in therate and extent to which the active ingredient or active moiety inpharmaceutical equivalents or pharmaceutical alternatives becomeavailable at the site of drug action when administered at the same molardose under similar conditions in an appropriately designed study.

When ranges are given by specifying the lower end of a range separatelyfrom the upper end of the range, it will be understood that the rangecan be defined by selectively combining any one of the lower endvariables with any one of the upper end variables that is mathematicallyand physically possible. Thus, for example, if a formulation may containfrom 1 to 10 weight parts of a particular ingredient, or 2 to 8 parts ofa particular ingredient, it will be understood that the formulation mayalso contain from 2 to 10 parts of the ingredient. In like manner, if aformulation may contain greater than 1 or 2 weight parts of aningredient and up to 10 or 9 weight parts of the ingredient, it will beunderstood that the formulation may contain 1-10 weight parts of theingredient, 2-9 weight parts of the ingredient, etc. unless otherwisespecified, the boundaries of the range (lower and upper ends of therange) are included in the claimed range.

In like manner, when various sub-embodiments of a senior (i.e.principal) embodiment are described herein, it will be understood thatthe sub-embodiments for the senior embodiment can be combined to defineanother sub-embodiment. Thus, for example, when a principal embodimentincludes sub-embodiments 1, 2 and 3, it will be understood that theprincipal embodiment can be further limited by any one ofsub-embodiments 1, 2 and 3, or any combination of sub-embodiments 1, 2and 3 that is mathematically and physically possible. In like manner, itwill be understood that the principal embodiments described herein canbe combined in any manner that is mathematically and physicallypossible, and that the invention extends to such combinations.

When used herein the term “about” or “substantially” or “approximately”will compensate for variability allowed for in the pharmaceuticalindustry and inherent in pharmaceutical products, such as differences inproduct strength due to manufacturing variation and time-induced productdegradation. The term allows for any variation which in the practice ofpharmaceuticals would allow the product being evaluated to be consideredbioequivalent to the recited strength, as described in FDA's March 2003Guidance for Industry on BIOAVAILABILITY AND BIOEQUIVALENCE STUDIES FORORALLY ADMINISTERED DRUG PRODUCTS—GENERAL CONSIDERATIONS.

When used herein the term “gamma-hydroxybutyrate” or GHB, unlessotherwise specified, refers to the free base of gamma hydroxy-butyrate,a pharmaceutically acceptable salt of gamma-hydroxybutyric acid, andcombinations thereof, their hydrates, solvates, complexes or tautomersforms. Gamma-hydroxybutyric acid salts can be selected from the sodiumsalt of gamma-hydroxybutyric acid or sodium oxybate, the potassium saltof gamma-hydroxybutyric acid, the magnesium salt of gamma-hydroxybutyricacid, the calcium salt of gamma-hydroxybutyric acid, the lithium salt ofgamma-hydroxybutyric, the tetra ammonium salt of gamma-hydroxybutyricacid or any other pharmaceutically acceptable salt forms ofgamma-hydroxybutyric acid.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic and neitherbiologically nor otherwise undesirable and includes that which isacceptable for veterinary use as well as human pharmaceutical use. Theterm “formulation” or “composition” refers to the quantitative andqualitative characteristics of a drug product or dosage form prepared inaccordance with the current invention.

As used herein the doses and strengths of gamma-hydroxybutyrate areexpressed in equivalent-gram (g) weights of sodium oxybate unless statedexpressly to the contrary. Thus, when considering a dose ofgamma-hydroxybutyrate other than the sodium salt ofgamma-hydroxybutyrate, one must convert the recited dose or strengthfrom sodium oxybate to the gamma-hydroxybutyrate under evaluation. Thus,if an embodiment is said to provide a 4.5 g dose ofgamma-hydroxybutyrate, because the form of gamma-hydroxybutyrate is notspecified, it will be understood that the dose encompasses a 4.5 g doseof sodium oxybate, a 5.1 g dose of potassium gamma-hydroxybutyrate(assuming a 126.09 g/mol MW for sodium oxybate and a 142.20 g/mol MW forpotassium gamma-hydroxybutyrate), and a 3.7 g dose of the free base(assuming a 126.09 g/mol MW for sodium oxybate and a 104.1 g/mol MW forthe free base of gamma-hydroxybutyrate), or by the weight of any mixtureof salts of gamma-hydroxybutyric acid that provides the same amount ofGHB as 4.5 g of sodium oxybate.

As used herein “microparticle” means any discreet particle of solidmaterial. The particle can be made of a single material or have acomplex structure with core and shells and be made of several materials.The terms “microparticle”, “particle”, “microspheres” or “pellet” areinterchangeable and have the same meaning. Unless otherwise specified,the microparticle has no particular particle size or diameter and is notlimited to particles with volume mean diameter D(4,3) below 1 mm.

As used herein, the “volume mean diameter D(4,3)” is calculatedaccording to the following formula:

D(4,3)=Σ(d ⁴ _(i) ·n _(i))/Σ(d ³ _(i) ·n _(i))

wherein the diameter d of a given particle is the diameter of a hardsphere having the same volume as the volume of that particle.

As used herein, the terms “finished composition”, “finished formulation”or “formulation” are interchangeable and designate the modified releaseformulation of gamma-hydroxybutyrate preferably comprising modifiedrelease microparticles of gamma-hydroxybutyrate, immediate releasemicroparticles of gamma-hydroxybutyrate, and any other excipients.

As used herein and in the claims that follow, an “immediate release (IR)portion” of a formulation includes physically discreet portions of aformulation, mechanistically discreet portions of a formulation, andpharmacokinetically discreet portions of a formulation that lend to orsupport a defined IR pharmacokinetic characteristic. Thus, for example,any formulation that releases active ingredient at the rate and extentrequired of the immediate release portion of the formulations of thepresent invention includes an “immediate release portion,” even if theimmediate release portion is physically integrated in what mightotherwise be considered an extended release formulation. Thus, the IRportion can be structurally discreet or structurally indiscreet from(i.e. integrated with) the MR portion. In a preferred embodiment, the IRportion and MR portion are provided as particles, and in an even morepreferred subembodiment the IR portion and MR portion are provided asparticles discreet from each other.

As used here in, “immediate release formulation” or “immediate releaseportion” refers to a composition that releases at least 80% of itsgamma-hydroxybutyrate in 1 hour when tested in a dissolution apparatus 2according to USP 38 <711> in a 0.1N HCl dissolution medium at atemperature of 37° C. and a paddle speed of 75 rpm.

In like manner, a “modified-release (MR) portion” includes that portionof a formulation or dosage form that lends to or supports a particularMR pharmacokinetic characteristic, regardless of the physicalformulation in which the MR portion is integrated. The modified releasedrug delivery systems are designed to deliver drugs at a specific timeor over a period of time after administration, or at a specific locationin the body. The USP defines a modified release system as one in whichthe time course or location of drug release or both, are chosen toaccomplish objectives of therapeutic effectiveness or convenience notfulfilled by conventional IR dosage forms. More specifically, MR solidoral dosage forms include extended release (ER) and delayed-release (DR)products. A DR product is one that releases a drug all at once at a timeother than promptly after administration. Typically, coatings (e.g.,enteric coatings) are used to delay the release of the drug substanceuntil the dosage form has passed through the acidic medium of thestomach. An ER product is formulated to make the drug available over anextended period after ingestion, thus allowing a reduction in dosingfrequency compared to a drug presented as a conventional dosage form,e.g. a solution or an immediate release dosage form. For oralapplications, the term “extended-release” is usually interchangeablewith “sustained-release”, “prolonged-release” or “controlled-release”.

Traditionally, extended-release systems provided constant drug releaseto maintain a steady concentration of drug. For some drugs, however,zero-order delivery may not be optimal and more complex andsophisticated systems have been developed to provide multiphasedelivery. One can distinguish among four categories of oral MR deliverysystems: (1) delayed-release using enteric coatings, (2) site-specificor timed release (e.g. for colonic delivery), (3) extended-release(e.g., zero-order, first-order, biphasic release, etc.), and (4),programmed release (e.g., pulsatile, delayed extended release, etc.) SeeModified Oral Drug Delivery Systems at page 34 in Gibaldi's DRUGDELIVERY SYSTEMS IN PHARMACEUTICAL CARE, AMERICAN SOCIETY OFHEALTH-SYSTEM PHARMACISTS, 2007 and Rational Design of OralModified-release Drug Delivery Systems at page 469 in DEVELOPING SOLIDORAL DOSAGE FORMS: PHARMACEUTICAL THEORY AND PRACTICE, Academic Press,Elsevier, 2009. As used herein, “modified release formulation” or“modified release portion” in one embodiment refers to a compositionthat releases its gamma-hydroxybutyrate according a multiphase deliverythat is comprised in the fourth class of MR products, e.g. delayedextended release. As such it differs from the delayed release productsthat are classified in the first class of MR products.

As used herein the terms “coating”, “coating layer,” “coating film,”“film coating” and like terms are interchangeable and have the samemeaning. The terms refer to the coating applied to a particle comprisingthe gamma-hydroxybutyrate that controls the modified release of thegamma-hydroxybutyrate.

In all pharmacokinetic testing described herein, unless otherwisestated, the dosage form, or the initial dosage form if the dosingregimen calls for more than one administration, is administeredapproximately two hours after consumption of a standardized dinnerconsisting of 25.5% fat, 19.6% protein, and 54.9% carbohydrates.

A “similar PK profile” or “comparable bioavailability” means that themean AUC_(inf) of a test product is from 80% to 125% of the meanAUC_(inf) of a reference product in a suitably designed cross-overtrial, and that the mean plasma concentration at 8 hours (C_(h)) of thetest product is from 50% to 130% of the mean plasma concentration at 8hours (C_(8h)) of the reference product.

Type 1 Narcolepsy (NT1) refers to narcolepsy characterized by excessivedaytime sleepiness (“EDS”) and cataplexy. Type 2 Narcolepsy (NT2) refersto narcolepsy characterized by excessive daytime sleepiness withoutcataplexy. A diagnosis of narcolepsy (with or without cataplexy) can beconfirmed by one or a combination of (i) an overnight polysomnogram(PSG) and a Multiple Sleep Latency Test (MSLT) performed within the last2 years, (ii) a full documentary evidence confirming diagnosis from thePSG and MSLT from a sleep laboratory must be made available, (iii)current symptoms of narcolepsy including: current complaint of EDS forthe last 3 months (ESS greater than 10), (iv) mean MWT less than 8minutes, (v) mean number of cataplexy events of 8 per week on baselineSleep/Cataplexy Diary, and/or (vi) presence of cataplexy for the last 3months and 28 events per week during screening period.

Unless otherwise specified herein, percentages, ratios and numericvalues recited herein are based on weight; averages and means arearithmetic means; all pharmacokinetic measurements based on themeasurement of bodily fluids are based on plasma concentrations.

It will be understood, when defining a composition by itspharmacokinetic or dissolution properties herein, that the formulationcan in the alternative be defined as “means for” achieving the recitedpharmacokinetic or dissolution properties. Thus, a formulation in whichthe modified release portion releases less than 20% of itsgamma-hydroxybutyrate at one hour can instead be defined as aformulation comprising “means for” or “modified release means for”releasing less than 20% of its gamma-hydroxybutyrate at one hour. Itwill be further understood that the preferred structures for achievingthe recited pharmacokinetic or dissolution properties are the structuresdescribed in the examples hereof that accomplish the recitedpharmacokinetic or dissolution properties.

Discussion of Principal Embodiments

The invention can be described in terms of principal embodiments, whichin turn can be recombined to make other principal embodiments, andlimited by sub-embodiments to make other principal embodiments.

A first principal embodiment of the present invention provides amodified release formulation of gamma-hydroxybutyrate, preferablycomprising immediate release and modified release portions, wherein a7.5 g dose of the formulation has been shown to achieve a mean AUC_(inf)of greater than 245, 300, 325, 340, 375, 400, 425, or 450hr×microgram/mL, most preferably greater than 340 hr×microgram/mL.

A second principal embodiment of the present invention provides amodified release formulation of gamma-hydroxybutyrate, preferablycomprising immediate release and modified release portions, wherein a7.5 g dose of the formulation has been shown to achieve a mean AUC_(inf)of greater than 245, 265, 285, 300, 315, 325, 340, 350, 375, 400, 425,or 450 hr×microgram/mL, most preferably greater than 340hr×microgram/mL, and a mean C_(8h) that is from 50% to 130%, from 60% to130%, from 70% to 130%, from 75% to 125%, from 80% to 125%, from 80 to120%, from 90% to 110%, from 50% to 95%, from 60% to 90%, mostpreferably from 60% to 90% or 60% to 130% of the mean C_(8h) provided byan equal dose of an immediate release liquid solution of sodium oxybate(e.g. Xyrem®) administered at t₀ and t_(4h) in equally divided dosesapproximately two hours after a standardized evening meal.

A third principal embodiment of the present invention provides amodified release formulation of gamma-hydroxybutyrate, preferablycomprising immediate release and modified release portions, wherein theformulation releases (a) at least 80% or 90% of itsgamma-hydroxybutyrate at 3 hours, 2 hours, 1 hour, 0.5 hours, or 0.25hours, preferably 1 hour, when tested in a dissolution apparatus 2according to USP 38 <711> in 900 mL of 0.05M monobasic potassiumphosphate buffer pH 6.8 at a temperature of 37° C. and a paddle speed of75 rpm, and (b) from 10 to 65%, from 15 to 60%, from 20 to 55%, from 25to 55%, from 30 to 55%, from 35 to 55%, from 40 to 55%, from 40 to 60%,or from 45 to 55%, preferably from 40% to 60%, of itsgamma-hydroxybutyrate at one hour and three hours when tested in adissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1Nhydrochloric acid at a temperature of 37° C. and a paddle speed of 75rpm.

A fourth principal embodiment of the present invention provides amodified release formulation of gamma-hydroxybutyrate, comprisingimmediate release and modified release portions, wherein (a) theformulation releases at least 80% or 90% of its gamma-hydroxybutyrate at3 hours, 2 hours, 1 hour, 0.5 hours, or 0.25 hours, preferably 1 hour,when tested in a dissolution apparatus 2 according to USP 38 <711> in900 mL of 0.05M monobasic potassium phosphate buffer pH 6.8 at atemperature of 37° C. and a paddle speed of 75 rpm, (b) the formulationreleases from 10 to 65%, from 15 to 60%, from 20 to 55%, from 25 to 55%,from 30 to 55%, from 35 to 55%, from 40 to 55%, from 40 to 60%, or from45 to 55%, preferably from 40% to 60%, of its gamma-hydroxybutyrate atone hour and at three hours when tested in a dissolution apparatus 2according to USP 38 <711> in 900 mL of 0.1N hydrochloric acid at atemperature of 37° C. and a paddle speed of 75 rpm, and (c) the modifiedrelease portion preferably releases greater than 80% or 90% of itsgamma-hydroxybutyrate at 3 hours in a dissolution test started in 750 mLof 0.1N hydrochloric acid for 2 hours then switched to 950 mL 0.05Mmonobasic potassium phosphate buffer adjusted to pH 6.8 at a temperatureof 37° C. and a paddle speed of 75 rpm.

A fifth principal embodiment of the present invention provides amodified release formulation of gamma-hydroxybutyrate, comprisingimmediate release and modified release portions, wherein (a) theformulation releases at least 80% or 90% of its gamma-hydroxybutyrate at3 hours, 2 hours, 1 hour, 0.5 hours, or 0.25 hours, preferably 1 hour,when tested in a dissolution apparatus 2 according to USP 38 <711> in900 mL of 0.05M monobasic potassium phosphate buffer pH 6.8 at atemperature of 37° C. and a paddle speed of 75 rpm, (b) the formulationreleases from 10 to 65%, from 15 to 60%, from 20 to 55%, from 25 to 55%,from 30 to 55%, from 35 to 55%, from 40 to 55%, from 40 to 60%, or from45 to 55%, preferably from 40% to 60%, of its gamma-hydroxybutyrate atone hour and at three hours when tested in a dissolution apparatus 2according to USP 38 <711> in 900 mL of 0.1N hydrochloric acid at atemperature of 37° C. and a paddle speed of 75 rpm, (c) the formulationreleases greater than 60%, 70%, or 80%, preferably greater than 80%, ofits gamma-hydroxybutyrate at 10 hours when tested in a dissolutionapparatus 2 according to USP 38 <711> in 900 mL of 0.1N hydrochloricacid at a temperature of 37° C. and a paddle speed of 75 rpm, and (d)the modified release portion releases greater than 80% of itsgamma-hydroxybutyrate at 3 hours in a dissolution test started in 750 mLof 0.1N hydrochloric acid for 2 hours then switched to 950 mL 0.05Mmonobasic potassium phosphate buffer adjusted to pH 6.8 at a temperatureof 37° C. and a paddle speed of 75 rpm.

A sixth principal embodiment of the present invention provides amodified release formulation of gamma-hydroxybutyrate, comprisingimmediate release and modified release portions, wherein (a) a 7.5 gdose of the formulation has been shown to achieve a mean AUC_(inf) ofgreater than 245, 300, 325, 340, 375, 400, 425, or 450 hr×microgram/mL,preferably 340 hr×microgram/mL, and a mean C_(8h) that is from 50% to130%, from 60% to 130%, from 70% to 130%, from 75% to 125%, from 80% to125%, from 80 to 120%, from 90% to 110%, from 50% to 95%, or from 60% to90%, preferably from 60% to 90% or from 60% to 130%, of the mean C_(8h)provided by an equal dose of an immediate release liquid solution ofgamma-hydroxybutyrate (e.g. Xyrem®) administered at t₀ and t_(4h) inequally divided doses approximately two hours after a standardizedevening meal, and (b) the formulation releases (i) at least 80% or 90%of its gamma-hydroxybutyrate at 3 hours, 2 hours, 1 hour, 0.5 hours, or0.25 hours, preferably 1 hour, when tested in a dissolution apparatus 2according to USP 38 <711> in 900 mL of 0.05M monobasic potassiumphosphate buffer pH 6.8 at a temperature of 37° C. and a paddle speed of75 rpm, and (ii) from 10 to 65%, from 15 to 60%, from 20 to 55%, from 25to 55%, from 30 to 55%, from 35 to 55%, from 40 to 55%, from 40 to 60%,or from 45 to 55%, preferably from 40% to 60%, of itsgamma-hydroxybutyrate at one hour and three hours when tested in adissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1Nhydrochloric acid at a temperature of 37° C. and a paddle speed of 75rpm, and (c) the modified release portion releases greater than 80% ofits gamma-hydroxybutyrate at 3 hours in a dissolution test started in750 mL of 0.1N hydrochloric acid for 2 hours then switched to 950 mL0.05M monobasic potassium phosphate buffer adjusted to pH 6.8 at atemperature of 37° C. and a paddle speed of 75 rpm.

A seventh principal embodiment of the present invention provides amodified release formulation of gamma-hydroxybutyrate comprisingimmediate release and modified release portions, wherein: (a) saidimmediate release portion releases greater than 80% or 90% of itsgamma-hydroxybutyrate at one hour when tested in a dissolution apparatus2 according to USP 38 <711> in 900 mL of 0.1N hydrochloric acid at atemperature of 37° C. and a paddle speed of 75 rpm; (b) said modifiedrelease portion releases less than 20% or 10% of itsgamma-hydroxybutyrate at one hour when tested in a dissolution apparatus2 according to USP 38 <711> in 900 mL of 0.1N hydrochloric acid at atemperature of 37° C. and a paddle speed of 75 rpm; and (c) saidmodified release portion releases greater than 80% or 90% of itsgamma-hydroxybutyrate at three hours, two hours or one hour, when testedin a dissolution apparatus 2 according to USP 38 <711> in 900 mL of0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of37° C. and a paddle speed of 75 rpm.

An eighth principal embodiment of the present invention provides amodified release formulation of gamma-hydroxybutyrate comprisingimmediate release and modified release portions, wherein: (a) saidimmediate release portion releases greater than 80% or 90% of itsgamma-hydroxybutyrate at one hour, two hours, or three hours when testedin a dissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1Nhydrochloric acid at a temperature of 37° C. and a paddle speed of 75rpm; (b) said modified release portion releases less than 20% or 10% ofits gamma-hydroxybutyrate at one hour when tested in a dissolutionapparatus 2 according to USP 38 <711> in 900 mL of 0.1N hydrochloricacid at a temperature of 37° C. and a paddle speed of 75 rpm; (c) saidmodified release portion releases greater than 80% or 90% of itsgamma-hydroxybutyrate at three hours, two hours, or one hour, whentested in a dissolution apparatus 2 according to USP 38 <711> in 900 mLof 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of37° C. and a paddle speed of 75 rpm; and (d) said modified releaseportion releases greater than 80% or 90% of its gamma-hydroxybutyrate at3 hours in a dissolution test started in 750 mL of 0.1N hydrochloricacid for 2 hours then switched to 950 mL 0.05M monobasic potassiumphosphate buffer adjusted to pH 6.8 at a temperature of 37° C. and apaddle speed of 75 rpm.

A ninth principal embodiment of the present invention provides amodified release formulation of gamma-hydroxybutyrate, preferablycomprising immediate release and modified release portions, wherein a4.5 g, 6 g, 7.5 g, and 9 g dose of the formulation has been shown toachieve a relative bioavailability (RBA) of greater than 80%, 85% or 90%when compared to an equal dose of an immediate release liquid solutionof sodium oxybate administered at t₀ and t_(4h) in equally divideddoses, when administered approximately two hours after a standardizedevening meal. The relative bioavailability is even higher with largerdoses, and with a 6.0 g or 7.5 g or 9.0 g dose is preferably greaterthan 90, 95 or 100% when compared to an equal dose of an immediaterelease liquid solution of sodium oxybate administered at t₀ and t_(4h)in equally divided doses, when administered approximately two hoursafter a standardized evening meal.

A tenth principal embodiment of the present invention provides amodified release formulation of gamma-hydroxybutyrate, wherein a 4.5 gand a 9 g dose of the formulation has been shown to achieve a relativebioavailability (RBA) of greater than 80% when compared to an equal doseof an immediate release liquid solution of sodium oxybate administeredat t₀ and t_(4h) in equally divided doses, when administeredapproximately two hours after a standardized evening meal.

An eleventh principal embodiment of the present invention provides amodified release formulation of gamma-hydroxybutyrate, preferablycomprising immediate release and modified release portions, that yieldsa plasma concentration versus time curve when administered once nightlyat a strength of 4.5 g, 6.0 g, or 7.5 g approximately two hours after astandardized evening meal substantially as depicted in FIG. 12 or FIG.13 for the corresponding strength.

A twelfth principal embodiment of the present invention provides amodified release formulation of gamma-hydroxybutyrate, preferablycomprising immediate release and modified release portions, that yieldsa plasma concentration versus time curve when administered once nightlyat a strength of 4.5 g approximately two hours after a standardizedevening meal substantially as depicted in FIG. 22.

A thirteenth principal embodiment of the present invention provides amodified release formulation of gamma-hydroxybutyrate, preferablycomprising immediate release and modified release portions, that yieldsa dissolution profile substantially as depicted in FIG. 7 and FIG. 8.

A fourteenth principal embodiment of the present invention provides amodified release formulation of gamma-hydroxybutyrate, preferablycomprising immediate release and modified release portions, that yieldsa dissolution profile substantially as depicted in FIG. 20 and FIG. 21.

A fifteenth principal embodiment of the present invention provides amodified release formulation of gamma-hydroxybutyrate, preferablycomprising immediate release and modified release portions that yields adissolution profile substantially as depicted in FIG. 3 or 16.

In a sixteenth principal embodiment, the invention provides a modifiedrelease formulation of gamma-hydroxybutyrate, comprising immediaterelease and modified release portions that yields a dissolution profilebetween the minimum and maximum values depicted in FIG. 25 and FIG. 26.

In a seventeenth principal embodiment, the invention provides a modifiedrelease formulation of gamma-hydroxybutyrate, comprising immediaterelease and modified release portions that yields a dissolution profilebetween the minimum and maximum values depicted in FIG. 27 and FIG. 28.

In an eighteenth principal embodiment the invention provides a modifiedrelease formulation of gamma-hydroxybutyrate yielding a dissolutionprofile substantially as shown in any one of FIGS. 29 through 89. Itwill be understood that this seventeenth principal embodiment can belimited only to one of these dissolution profiles.

A nineteenth principal embodiment of the present invention provides amodified release formulation of gamma-hydroxybutyrate, preferablycomprising immediate release and modified release portions, that yieldsa plasma concentration versus time curve when administered once nightlyat a strength of 4.5 g, 7.5 g or 9.0 g approximately two hours after astandardized evening meal substantially as depicted in FIG. 90 for thecorresponding strength.

In any of these principal embodiments, the formulation is preferablyeffective to treat narcolepsy Type 1 or Type 2. The formulation is alsopreferably effective to induce sleep for six to eight, most preferablyeight consecutive hours.

In any of these principal embodiments, the formulation preferablycomprises immediate release and modified release portions, wherein themodified release portion comprises gamma hydroxybutyrate particlescoated by a polymer carrying free carboxylic groups and a hydrophobiccompound having a melting point equal or greater than 40° C., and theratio of gamma-hydroxybutyrate in the immediate release portion and themodified release portion is from 10/90 to 65/35. The polymers comprisingfree carboxylic groups preferably have a pH dissolution trigger of from5.5 to 6.97 and are preferably methacrylic acid copolymers having a pHdissolution trigger of from 5.5 to 6.97.

Principal Structural Embodiments

In a first principal structural embodiment, the invention provides amodified release formulation of gamma-hydroxybutyrate comprisingimmediate release and modified release portions, wherein: (a) themodified release portion comprises coated particles ofgamma-hydroxybutyrate; (b) the coating comprises a polymer carrying freecarboxylic groups and a hydrophobic compound having a melting pointequal or greater than 40° C.; and (c) the ratio of gamma-hydroxybutyratein the immediate release portion and the modified release portion isfrom 10/90 to 65/35.

In a second principal structural embodiment the invention provides amodified release formulation of gamma-hydroxybutyrate comprisingimmediate release and modified release portions, a suspending orviscosifying agent, and an acidifying agent, wherein: (a) the modifiedrelease portion comprises coated particles of gamma-hydroxybutyrate; (b)the coating comprises a polymer carrying free carboxylic groups and ahydrophobic compound having a melting point equal or greater than 40°C.; and (c) the ratio of gamma-hydroxybutyrate in the immediate releaseportion and the modified release portion is from 10/90 to 65/35.

In a third principal structural embodiment the invention provides amodified release formulation of gamma-hydroxybutyrate comprisingimmediate release and modified release portions, wherein: (a) themodified release portion comprises coated particles ofgamma-hydroxybutyrate; (b) the coating comprises a polymer carrying freecarboxylic groups and a hydrophobic compound having a melting pointequal or greater than 40° C.; (c) the weight ratio of the hydrophobiccompound to the polymer carrying free carboxylic groups is from 0.4 to4; (d) the ratio of gamma-hydroxybutyrate in the immediate releaseportion and the modified release portion is from 10/90 to 65/35; and (e)the coating is from 10 to 50% of the weight of the particles.

In a fourth principal structural embodiment the invention provides amodified release formulation of gamma-hydroxybutyrate comprisingimmediate release and modified release portions, wherein: (a) themodified release portion comprises coated particles ofgamma-hydroxybutyrate; (b) the coating comprises a polymer carrying freecarboxylic groups having a pH trigger of from 5.5 to 6.97 and ahydrophobic compound having a melting point equal or greater than 40°C.; (c) the weight ratio of the hydrophobic compound to the polymercarrying free carboxylic groups is from 0.4 to 4; (d) the ratio ofgamma-hydroxybutyrate in the immediate release portion and the modifiedrelease portion is from 10/90 to 65/35; and (e) the coating is from 10to 50% of the weight of the particles.

In a fifth principal structural embodiment the invention provides amodified release formulation of gamma-hydroxybutyrate comprisingimmediate release and modified release portions, wherein: (a) themodified release portion comprises coated particles ofgamma-hydroxybutyrate; (b) the coating comprises a methacrylic acidcopolymer carrying free carboxylic groups having a pH trigger of from5.5 to 6.97 and a hydrophobic compound having a melting point equal orgreater than 40° C.; (c) the weight ratio of the hydrophobic compound tothe polymer carrying free carboxylic groups is from 0.4 to 4; (d) theratio of gamma-hydroxybutyrate in the immediate release portion and themodified release portion is from 10/90 to 65/35; and (e) the coating isfrom 10 to 50% of the weight of the particles.

Discussion of Pharmacokinetic and Dissolution Sub-Embodiments

As mentioned in the definitions section of this document, each of thesub-embodiments can be used to further characterize and limit each ofthe foregoing principal embodiments. In addition, more than one of thefollowing sub-embodiments can be combined and used to furthercharacterize and limit each of the foregoing principal embodiments, inany manner that is mathematically and physically possible.

In various sub-embodiments of the foregoing principal embodiments a 7.5g dose of the modified release formulation of gamma-hydroxybutyrate canbe characterized as having been shown to achieve a mean AUC_(inf) ofgreater than 245, 265, 285, 300, 315, 325, 340, 350, 375, 400, 425, or450 hr×microgram/mL when administered once approximately two hours aftera standardized evening meal. An upper limit on mean AUC_(inf) for such7.5 g dose can be set at 500 or 550 hr×microgram/mL.

In additional sub-embodiments of the foregoing principal embodiments a7.5 g dose of the modified release formulation of gamma-hydroxybutyratecan be characterized as having been shown to achieve a mean C_(max) ofgreater than 65, 70, 75, 80, 85, or 90 microgram/mL when administeredonce approximately two hours after a standardized evening meal. An upperlimit on mean C_(max) for such 7.5 g dose can be set at 125 or 100microgram/mL.

In additional sub-embodiments of the forgoing principal embodiments a7.5 g dose of the modified release formulation of gamma-hydroxybutyratecan be characterized as having been shown to achieve a mean C_(8h) thatis from 50% to 130%, from 60% to 130%, from 70 to 130%, from 75% to125%, from 80% to 125%, from 80 to 120%, or from 90% to 110% of the meanC_(8h) provided by an equal dose of immediate release liquid solution ofgamma-hydroxybutyrate administered at t₀ and t_(4h) in two equallydivided doses, when administered approximately two hours after astandardized evening meal.

In one sub-embodiment, a 7.5 g dose of the formulation has been shown toachieve a mean AUC_(inf) of greater than 340 hr·microgram/mL, and a meanC_(8h) that is from 50% to 130% of the mean C_(8h) provided by an equaldose of immediate release liquid solution of sodium oxybate administeredat t₀ and t_(4h) in equally divided doses approximately two hours aftera standardized evening meal.

Further sub-embodiments can be characterized based on the dissolutionproperties of the entire (or finished) modified release formulation ofgamma-hydroxybutyrate in 0.1N hydrochloric acid dissolution medium.Thus, in additional sub-embodiments the entire modified releaseformulation of gamma-hydroxybutyrate releases greater than 30%, 35%,40%, or 45%, and less than 70%, 65%, 60%, or 55%, of itsgamma-hydroxybutyrate at one hour when tested in a dissolution apparatus2 according to USP 38 <711> in 900 mL of 0.1N hydrochloric acid at atemperature of 37° C. and a paddle speed of 75 rpm.

Further sub-embodiments can be defined based on the dissolutionproperties of the modified release portion of the formulation ofgamma-hydroxybutyrate in a phosphate buffer pH 6.8 dissolution medium.Thus, in additional sub-embodiments the modified release portionreleases greater than 80%, 85%, 90%, 95%, 98% or even 99% of itsgamma-hydroxybutyrate at 3, 2, 1, 0.5 or 0.25 hours when tested in adissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.05Mmonobasic potassium phosphate buffer pH 6.8 at a temperature of 37° C.and a paddle speed of 75 rpm.

Still further embodiments can be defined based on the dissolutionproperties of the modified release portion of the modified releaseformulation of gamma-hydroxybutyrate in a 0.1N HCl dissolution medium.Thus, in additional sub-embodiments the modified release portionreleases less than 20%, 15%, 10%, 5%, or even 2% of itsgamma-hydroxybutyrate at one hour when tested in a dissolution apparatus2 according to USP 38 <711> in 900 mL of 0.1N hydrochloric acid at atemperature of 37° C. and a paddle speed of 75 rpm.

In additional embodiments, the modified release portion releases lessthan 20%, 15%, 10%, 5%, or even 2% of its gamma-hydroxybutyrate at onehour and at three hours and more than 30%, 35%, 40%, 45% of itsgamma-hydroxybutyrate at ten hours when tested in a dissolutionapparatus 2 according to USP 38 <711> in 900 mL of 0.1N hydrochloricacid at a temperature of 37° C. and a paddle speed of 75 rpm.

Further embodiments can be defined based on the dissolution propertiesof the immediate release portion of the modified release formulation ofgamma-hydroxybutyrate in a 0.1N HCl dissolution medium. Thus, inadditional sub-embodiments the immediate release portion releasesgreater than 80%, 85%, 90%, 95%, 98% or even 99% of itsgamma-hydroxybutyrate at one hour when tested in a dissolution apparatus2 according to USP 38 <711> in 900 mL of 0.1N hydrochloric acid at atemperature of 37° C. and a paddle speed of 75 rpm.

In another sub-embodiment, the formulation releases (a) at least 80% ofits gamma-hydroxybutyrate at three hours when tested in a dissolutionapparatus 2 according to USP 38 <711> in 900 mL of 0.05M monobasicpotassium phosphate buffer pH 6.8 at a temperature of 37° C. and apaddle speed of 75 rpm, and (b) from 10% to 65%, of itsgamma-hydroxybutyrate at one hour and three hours when tested in adissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1Nhydrochloric acid at a temperature of 37° C. and a paddle speed of 75rpm.

In another subembodiment, the formulation comprises immediate releaseand modified release portions, and (a) the formulation releases at least80% of its gamma-hydroxybutyrate at 3 hours when tested in a dissolutionapparatus 2 according to USP 38 <711> in 900 mL of 0.05M monobasicpotassium phosphate buffer pH 6.8 at a temperature of 37° C. and apaddle speed of 75 rpm, (b) the formulation releases from 10% to 65%, ofits gamma-hydroxybutyrate at one hour when tested in a dissolutionapparatus 2 according to USP 38 <711> in 900 mL of 0.1N hydrochloricacid at a temperature of 37° C. and a paddle speed of 75 rpm, and (c)the modified release portion releases greater than 80% of itsgamma-hydroxybutyrate at 3 hours in a dissolution test started in 750 mLof 0.1N hydrochloric acid for 2 hours then switched to 950 mL 0.05Mmonobasic potassium phosphate buffer adjusted to pH 6.8 at a temperatureof 37° C. and a paddle speed of 75 rpm.

In another sub-embodiment, the formulation comprises immediate releaseand modified release portions, and (a) the formulation releases at least80% of its gamma-hydroxybutyrate at 3 hours when tested in a dissolutionapparatus 2 according to USP 38 <711> in 900 mL of 0.05M monobasicpotassium phosphate buffer pH 6.8 at a temperature of 37° C. and apaddle speed of 75 rpm, (b) the formulation releases 10% to 65% of itsgamma-hydroxybutyrate at one hour and at three hours when tested in adissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1Nhydrochloric acid at a temperature of 37° C. and a paddle speed of 75rpm, (c) the formulation releases greater than 60% of itsgamma-hydroxybutyrate at 10 hours when tested in a dissolution apparatus2 according to USP 38 <711> in 900 mL of 0.1N hydrochloric acid at atemperature of 37° C. and a paddle speed of 75 rpm, and (d) the modifiedrelease portion releases greater than 80% of its gamma-hydroxybutyrateat 3 hours in a dissolution test started in 750 mL of 0.1N hydrochloricacid for 2 hours then switched to 950 mL 0.05M monobasic potassiumphosphate buffer adjusted to pH 6.8 at a temperature of 37° C. and apaddle speed of 75 rpm.

Still further sub-embodiments can be defined based on a pharmacokineticcomparison of the modified release formulation of gamma-hydroxybutyrateto an immediate release solution of gamma-hydroxybutyrate. Therefore, inadditional sub-embodiments the modified release formulation ofgamma-hydroxybutyrate, preferably in a 4.5 g, 6.0 g, 7.5 g, and 9.0 gdose, has been shown to achieve a relative bioavailability (RBA) ofgreater than 80%, 85%, 90%, or 95% when compared to an equal dose of animmediate release liquid solution of sodium oxybate administered at t₀and t_(4h) in equally divided doses, when administered approximately twohours after a standardized evening meal.

In additional sub-embodiments of the forgoing principal embodiments theinvention provides a modified release formulation ofgamma-hydroxybutyrate, preferably comprising immediate release andmodified release portions, wherein a 4.5 g and 9 g dose of theformulation has been shown to achieve a relative bioavailability (RBA)of greater than 80%, 85% or 90% when compared to an equal dose of animmediate release liquid solution of sodium oxybate administered at t₀and t_(4h) in equally divided doses, when administered approximately twohours after a standardized evening meal

In additional sub-embodiments, a 6.0 g or 7.5 g or 9.0 g dose of themodified release formulation of gamma-hydroxybutyrate has been shown toachieve a relative bioavailability (RBA) of greater than 80%, 85%, 90%,95% or 100% when compared to an equal dose of an immediate releaseliquid solution of sodium oxybate administered at t₀ and t_(4h) inequally divided doses, when administered approximately two hours after astandardized evening meal.

The modified release formulations of gamma-hydroxybutyrate of thepresent invention can also be defined by comparing the area under theconcentration/time curve for eight hours to the area under theconcentration/time curve calculated to infinity. Thus, in still furthersub-embodiments a 4.5 g, 6.0 g, 7.5 g or 9.0 g dose of the modifiedrelease formulation of gamma-hydroxybutyrate of the present inventionhas been shown to achieve a ratio of AUC_(8h) to AUC_(inf) of greaterthan 0.80, 0.85, 0.90, 0.95 or 0.98 when administered once approximatelytwo hours after a standardized evening meal.

In still further sub-embodiments, the modified release formulations ofgamma-hydroxybutyrate are defined based on the concentration ofgamma-hydroxybutyrate in the blood stream 8 hours after administration.Therefore, in other sub-embodiments the formulation can be characterizedby a 4.5 g dose of the modified release formulation ofgamma-hydroxybutyrate that has been shown to achieve a mean C_(8h) offrom 4.7 to 9.0, from 5.4 to 8.3, from 6.1 to 7.6, from 3.5 to 7.0, orfrom 4.0 to 5.5 microgram/mL, a 6.0 g dose of the modified releaseformulation of gamma-hydroxybutyrate has been shown to achieve a meanC_(8h) of from 6.3 to 16.7, from 7.3 to 15.4, from 8.2 to 14.1, from 8.9to 16.7, from 10.2 to 15.4, or from 11.5 to 14.1 microgram/mL; or a 7.5g dose of the modified release formulation of gamma-hydroxybutyrate hasbeen shown to achieve a mean C_(8h) of from 13.0 to 40.3, from 16.0 to26.0, 15.0 to 25.0, from 17.5 to 22.0, from 21.6 to 40.3, from 24.7 to37.2, or from 27.8 to 34.1 microgram/mL, when administered onceapproximately two hours after a standardized evening meal.

The modified release formulations of gamma-hydroxybutyrate of thepresent invention can also be defined by the concentration/time anddissolution curves that they produce when tested according to theexamples of the present invention. Therefore, in other sub-embodiments,a 4.5 g, 6.0 g, or 7.5 g dose of the modified release formulation ofgamma-hydroxybutyrate of the present invention has been shown to achievea time/concentration curve substantially as shown in FIGS. 13 (a), (b)and (c) respectively herein. In another principal embodiment orsub-embodiment, the formulation has been shown to achieve a dissolutioncurve substantially as shown in FIGS. 7 and 8 or FIGS. 20 and 21 herein.

The modified release formulations of gamma-hydroxybutyrate of thepresent invention can also be defined based on the time required toreach maximum blood concentration of gamma-hydroxybutyrate. Thus, inadditional sub-embodiments, the modified release formulation ofgamma-hydroxybutyrate has been shown to achieve a median T_(max) of 1.25to 3.25 hours, preferably of about 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75,3, or 3.25 hours when administered once approximately two hours after astandardized evening meal. A lower limit on the median T_(max) in any ofthe foregoing ranges can alternatively be set at 0.5 or 1.0 hours.

Additional embodiments can be defined by comparing a dose of themodified release formulation of gamma-hydroxybutyrate, administered oncenightly, to the same dose of an immediate release liquid solution ofsodium oxybate divided in half and administered twice nightly, 4 hoursapart. Thus, in another sub-embodiment a 4.5 g, 6.0 g, 7.5 g or 9.0 gdose of the modified release formulation of gamma-hydroxybutyrate hasbeen shown to achieve a median T_(max) within one hundred fifty, onehundred twenty, ninety, sixty or thirty minutes of the median T_(max) ofhalf the dose of an immediate release liquid solution of sodium oxybate,when administered approximately two hours after a standardized eveningmeal.

In still another sub-embodiment a 4.5 g, 6.0 g, 7.5 g or 9.0 g dose ofthe modified release formulation of gamma-hydroxybutyrate has been shownto achieve a mean C_(6h) or mean C_(7h) greater than, and a mean C_(10h)less than, the mean C_(4h) of half the dose of an immediate releaseliquid solution of sodium oxybate, when administered approximately twohours after a standardized evening meal.

Additional embodiments can be defined by comparing the pharmacokineticprofile of a dose of the modified release formulation ofgamma-hydroxybutyrate administered once nightly to the same dose of animmediate release liquid solution of sodium oxybate divided in half andadministered twice nightly, 4 hours apart. Thus, in anothersub-embodiment a modified release formulation of gamma-hydroxybutyrateaccording to the invention has been shown to achieve a ratio of its meanC_(3h) to the mean C_(max) of the first half dose of the immediaterelease liquid solution of sodium oxybate from 0.6 to 1.2, preferablyfrom 0.7 to 1.1 and most preferably from 0.8 to 1. In anothersub-embodiment, a modified release formulation of gamma-hydroxybutyrateaccording to the invention has been shown to achieve a ratio of its meanC_(4h) to the mean C_(max) of the first half dose of the immediaterelease liquid solution of sodium oxybate from 0.5 to 1.1, preferablyfrom 0.6 to 1 and most preferably from 0.7 to 0.9. In anothersub-embodiment, a modified release formulation of gamma-hydroxybutyrateaccording to the invention has been shown to achieve a ratio of its meanC_(4.5h) to the mean C_(max) of the first half dose of the immediaterelease liquid solution of gamma-hydroxybutyrate from 0.5 to 1,preferably from 0.5 to 0.9 and most preferably from 0.6 to 0.8.

Additional sub-embodiments can be defined by the range of mean bloodconcentrations of gamma-hydroxybutyrate achieved 3, 4, 4.5 or 5 hoursafter administration once nightly by a modified release formulation ofgamma-hydroxybutyrate according to the invention at the dose of 7.5 g.Thus, in another sub-embodiment, a 7.5 g dose of the modified releaseformulation of gamma-hydroxybutyrate has been shown to achieve a meanC_(3h) of 43 to 81 microgram/mL, preferably 49 to 75 microgram/mL andmore preferably 55 to 69 microgram/mL. In another sub-embodiment, a 7.5g dose of the modified release formulation of gamma-hydroxybutyrate hasbeen shown to achieve a mean C_(4h) of 40 to 75 microgram/mL, preferably45 to 69 microgram/mL and more preferably 51 to 64 microgram/mL. Inanother sub-embodiment, a 7.5 g dose of the modified release formulationof gamma-hydroxybutyrate has been shown to achieve a mean C_(4.5h) of 35to 67 microgram/mL, preferably 40 to 62 microgram/mL and more preferably45 to 56 microgram/mL. In another sub-embodiment, a 7.5 g dose of themodified release formulation of gamma-hydroxybutyrate has been shown toachieve a mean C_(5h) of 31 to 59 microgram/mL, preferably 36 to 55microgram/mL and more preferably 40 to 50 microgram/mL.

In another subembodiment, a 7.5 g dose of the formulation has been shownto achieve a mean AUC_(inf) of greater than 300 hr·microgram/mL and amean C_(max) of greater than 70 microgram/mL when administered onceapproximately two hours after a standardized evening meal.

In still another subembodiment, a 7.5 g dose of the formulation has beenshown to achieve a mean AUC_(inf) of greater than 350 hr·microgram/mLand a mean C_(max) of greater than 80 microgram/mL when administeredonce approximately two hours after a standardized evening meal.

In another subembodiment, a 4.5, 6.0, 7.5 and 9.0 g dose of theformulation has been shown to achieve a mean AUC_(inf) of greater than80% of the mean AUC_(inf) provided by an equal dose of immediate releaseliquid solution of sodium oxybate administered at t₀ and t_(4h) inequally divided doses approximately two hours after a standardizedevening meal, and a mean C_(8h) less than 95%, 90 or 85% of the meanC_(8h) provided by an equal dose of immediate release liquid solution ofsodium oxybate administered at t₀ and t_(4h) in equally divided dosesapproximately two hours after a standardized evening meal.

Additional embodiments can be defined by comparing the pharmacokineticprofile of a dose of the modified release formulation ofgamma-hydroxybutyrate administered once nightly to another dose of animmediate release liquid solution of sodium oxybate divided in half andadministered twice nightly, 4 hours apart. Thus, in anothersub-embodiment a 7.5 g dose of the modified release formulation ofgamma-hydroxybutyrate has been shown to achieve a similarpharmacokinetic profile to the pharmacokinetic profile provided by a2×4.5 g dose of sodium oxybate as an immediate release liquid solutionadministered for the first 4.5 g two hours after a standardized eveningmeal and for the second 4.5 g dose, 4 hours after the first dose. Thus,in another sub-embodiment a modified release formulation ofgamma-hydroxybutyrate according to the invention administered at thedose of 7.5 g has been shown to achieve a ratio of its mean C_(3h) tothe mean C_(max) of the first 4.5 g dose of the immediate release liquidsolution of sodium oxybate from 0.5 to 1.1, preferably from 0.6 to 1 andmost preferably from 0.7 to 0.9. In another sub-embodiment, a modifiedrelease formulation of gamma-hydroxybutyrate according to the inventionhas been shown to achieve a ratio of its mean C_(4h) to the mean C_(max)of the first 4.5 g dose of the immediate release liquid solution ofsodium oxybate from 0.5 to 1, preferably from 0.6 to 0.9 and mostpreferably from 0.7 to 0.8. In another sub-embodiment, a modifiedrelease formulation of gamma-hydroxybutyrate according to the inventionhas been shown to achieve a ratio of its mean C_(4.5h) to the meanC_(max) of the 4.5 g dose of the immediate release liquid solution ofsodium oxybate from 0.4 to 0.9, preferably from 0.5 to 0.8 and mostpreferably from 0.6 to 0.7.

In another subembodiment, the modified release formulation ofgamma-hydroxybutyrate comprises immediate release and modified releaseportions, wherein: (a) said immediate release portion releases greaterthan 80% of its gamma-hydroxybutyrate at one hour when tested in adissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1Nhydrochloric acid at a temperature of 37° C. and a paddle speed of 75rpm; (b) said modified release portion releases less than 20% of itsgamma-hydroxybutyrate at one hour when tested in a dissolution apparatus2 according to USP 38 <711> in 900 mL of 0.1N hydrochloric acid at atemperature of 37° C. and a paddle speed of 75 rpm; and (c) saidmodified release portion releases greater than 80% of itsgamma-hydroxybutyrate at one hour when tested in a dissolution apparatus2 according to USP 38 <711> in 900 mL of 0.05M monobasic potassiumphosphate buffer pH 6.8 at a temperature of 37° C. and a paddle speed of75 rpm.

In a preferred embodiment, the modified release formulation ofgamma-hydroxybutyrate according to the invention achieves an in vitrodissolution profile:

(a) measured in a dissolution apparatus 2 according to USP 38 <711> in900 mL of 0.1N hydrochloric acid at a temperature of 37° C. and a paddlespeed of 75 rpm, characterized by the percentage ofgamma-hydroxybutyrate dissolved being:

-   -   (i) from 40% to 65% at 1 hour,    -   (ii) from 40% to 65% at 3 hours,    -   (iii) from 47% to 85% at 8 hours,    -   (iv) greater or equal to 60% at 10 hours,    -   (v) greater or equal to 80% at 16 hours, and

(b) measured in a dissolution apparatus 2 according to USP 38 <711> in900 mL of 0.05M monobasic potassium phosphate buffer pH 6.8 at atemperature of 37° C. and a paddle speed of 75 rpm, characterized by thepercentage of gamma-hydroxybutyrate dissolved being:

-   -   (i) from 43% to 94% at 0.25 hour,    -   (ii) greater or equal to 65% at 0.35 hour, and    -   (iii) greater or equal to 88% at 1 hour.

In a preferred embodiment, the modified release formulation ofgamma-hydroxybutyrate according to the invention achieves an in vitrodissolution profile:

(a) measured in a dissolution apparatus 2 according to USP 38 <711> in900 mL of 0.1N hydrochloric acid at a temperature of 37° C. and a paddlespeed of 75 rpm, characterized by the percentage ofgamma-hydroxybutyrate dissolved being:

-   -   (i) from 40% to 65% at 1 hour,    -   (ii) from 40% to 65% at 3 hours,    -   (iii) greater or equal to 47% at 8 hours,    -   (iv) greater or equal to 60% at 10 hours,    -   (v) greater or equal to 80% at 16 hours, and

(b) measured in a dissolution apparatus 2 according to USP 38 <711> in900 mL of 0.05M monobasic potassium phosphate buffer pH 6.8 at atemperature of 37° C. and a paddle speed of 75 rpm, characterized by thepercentage of gamma-hydroxybutyrate dissolved being:

-   -   (i) from 43% to 94% at 0.25 hour,    -   (ii) greater or equal to 65% at 0.35 hour, and    -   (iii) greater or equal to 88% at 1 hour.

In another preferred embodiment, the modified release formulation ofgamma-hydroxybutyrate according to the invention achieves an in vitrodissolution profile:

(a) measured in a dissolution apparatus 2 according to USP 38 <711> in900 mL of 0.1N hydrochloric acid at a temperature of 37° C. and a paddlespeed of 75 rpm, characterized by the percentage ofgamma-hydroxybutyrate dissolved being:

-   -   (i) from 40% to 65% at 1 hour,    -   (ii) from 40% to 65% at 3 hours,    -   (iii) from 47% to 85% at 8 hours,    -   (iv) greater or equal to 60% at 10 hours,    -   (v) greater or equal to 80% at 16 hours, and

(b) measured in a dissolution apparatus 2 according to USP 38 <711> in900 mL of 0.05M monobasic potassium phosphate buffer pH 6.8 at atemperature of 37° C. and a paddle speed of 75 rpm, characterized by thepercentage of gamma-hydroxybutyrate dissolved being:

-   -   (i) from 45% to 67% at 1 hour, and    -   (ii) greater or equal to 65% at 3 hours.

In another preferred embodiment, the modified release formulation ofgamma-hydroxybutyrate according to the invention achieves an in vitrodissolution profile:

(a) measured in a dissolution apparatus 2 according to USP 38 <711> in900 mL of 0.1N hydrochloric acid at a temperature of 37° C. and a paddlespeed of 75 rpm, characterized by the percentage ofgamma-hydroxybutyrate dissolved being:

-   -   (i) from 40% to 65% at 1 hour,    -   (ii) from 40% to 65% at 3 hours,    -   (iii) greater or equal to 47% at 8 hours,    -   (iv) greater or equal to 60% at 10 hours,    -   (v) greater or equal to 80% at 16 hours, and

(b) measured in a dissolution apparatus 2 according to USP 38 <711> in900 mL of 0.05M monobasic potassium phosphate buffer pH 6.8 at atemperature of 37° C. and a paddle speed of 75 rpm, characterized by thepercentage of gamma-hydroxybutyrate dissolved being:

-   -   (i) from 45% to 67% at 1 hour, and    -   (ii) greater or equal to 65% at 3 hours.

In still another subembodiment, the formulation achieves an in vitrodissolution profile: (a) measured in a dissolution apparatus 2 accordingto USP 38 <711> in 900 mL of 0.1N hydrochloric acid at a temperature of37° C. and a paddle speed of 75 rpm, characterized by the percentage ofgamma-hydroxybutyrate dissolved being: (i) from 40% to 65% at 1 hour,(ii) from 40% to 65% at 3 hours, (iii) greater than 45% at 8 hours, and(b) measured in a dissolution apparatus 2 according to USP 38 <711> in900 mL of 0.05M monobasic potassium phosphate buffer pH 6.8 at atemperature of 37° C. and a paddle speed of 75 rpm, characterized by thepercentage of gamma-hydroxybutyrate dissolved being: (i) greater than40% at 0.5 hour, and (ii) greater than 85% at 1 hour.

Alternatively, the formulation can be described as achieving an in vitrodissolution profile measured in a dissolution apparatus 2 according toUSP 38 <711> in 900 mL of 0.1N hydrochloric acid at a temperature of 37°C. and a paddle speed of 75 rpm, characterized by the percentage ofgamma-hydroxybutyrate dissolved being: (i) from 40% to 65% at 1 hour,(ii) from 40% to 65% at 3 hours, and (iii) greater than 45% at 8 hours.

In another alternative, the formulation can be described as achieving anin vitro dissolution profile measured in a dissolution apparatus 2according to USP 38 <711> in 900 mL of 0.05M monobasic potassiumphosphate buffer pH 6.8 at a temperature of 37° C. and a paddle speed of75 rpm, characterized by the percentage of gamma-hydroxybutyratedissolved being: (i) greater than 40% at 0.5 hour, and (ii) greater than85% at 1 hour.

Structural Sub-Embodiments

The modified release formulations of gamma-hydroxybutyrate of thepresent invention can be provided in any dosage form that is suitablefor oral administration, including tablets, capsules, liquids, orallydissolving tablets, and the like, but they are preferably provided asdry particulate formulations (i.e. granules, powders, coated particles,microparticles, pellets, microspheres, etc.), in a sachet or othersuitable discreet packaging units. A preferred particulate formulationwill be mixed with tap water shortly before administration, preferably50 mL.

In one subembodiment, the formulation comprises immediate release andmodified release portions, wherein: (a) the modified release portioncomprises coated microparticles of gamma-hydroxybutyrate; and (b) theratio of gamma-hydroxybutyrate in the immediate release portion and themodified release portion is from 10/90 to 65/35.

In one subembodiment, the formulation comprises immediate release andmodified release portions, wherein: (a) the modified release portioncomprises coated microparticles of gamma-hydroxybutyrate; and (b) theratio of gamma-hydroxybutyrate in the immediate release portion and themodified release portion is from 40/60 to 60/40.

In another subembodiment, the formulation comprises immediate releaseand modified release portions, wherein: (a) the modified release portioncomprises coated microparticles of gamma-hydroxybutyrate; (b) thecoating of said modified release particles of gamma-hydroxybutyratecomprises a polymer carrying free carboxylic groups and a hydrophobiccompound having a melting point equal or greater than 40° C.; and (c)the ratio of gamma-hydroxybutyrate in the immediate release portion andthe modified release portion is from 10/90 to 65/35 or 40/60 to 60/40.

In another subembodiment, the formulation comprises immediate releaseand modified release portions, wherein: (a) the modified release portioncomprises coated microparticles of gamma-hydroxybutyrate; (b) thecoating of said modified release particles of gamma-hydroxybutyratecomprises a polymer carrying free carboxylic groups and a hydrophobiccompound having a melting point equal or greater than 40° C.; (c) theweight ratio of the hydrophobic compound to the polymer carrying freecarboxylic groups is from 0.4 to 4; (d) the ratio ofgamma-hydroxybutyrate in the immediate release portion and the modifiedrelease portion is from 10/90 to 65/35 or 40/60 to 60/40; and (e) thefilm coating is from 10 to 50% of the weight of the microparticles.

In another subembodiment the formulation comprises immediate release andmodified release portions, wherein: (a) the modified release portioncomprises coated particles of gamma-hydroxybutyrate; (b) the coating ofsaid modified release particles of gamma-hydroxybutyrate comprises apolymer carrying free carboxylic groups having a pH trigger of from 5.5to 6.97 and a hydrophobic compound having a melting point equal orgreater than 40° C.; (c) the weight ratio of the hydrophobic compound tothe polymer carrying free carboxylic groups is from 0.4 to 4; (d) theratio of gamma-hydroxybutyrate in the immediate release portion and themodified release portion is from 10/90 to 65/35 or 40/60 to 60/40; and(e) the coating is from 10 to 50% of the weight of the particles.

In a particularly preferred sub-embodiment of the immediately precedingsub-embodiments, the polymer carrying free carboxylic groups comprisesfrom 100% poly (methacrylic acid, ethyl acrylate) 1:1 and 0% poly(methacrylic acid, methylmethacrylate) 1:2 to 2% poly (methacrylic acid,ethyl acrylate) 1:1 and 98% poly (methacrylic acid, methylmethacrylate)1:2; and the hydrophobic compound comprises hydrogenated vegetable oil.

In a preferred embodiment, the formulation includes excipients toimprove the viscosity and the pourability of the mixture of theparticulate formulation with tap water. As such, the particulateformulation comprises, besides the immediate release and modifiedrelease particles of gamma-hydroxybutyrate, one or more suspending orviscosifying agents or lubricants.

Preferred suspending or viscosifying agents are chosen from the groupconsisting of xanthan gum, medium viscosity sodium carboxymethylcellulose, mixtures of microcrystalline cellulose and sodiumcarboxymethyl cellulose, mixtures of microcrystalline cellulose and guargum, medium viscosity hydroxyethyl cellulose, agar, sodium alginate,mixtures of sodium alginate and calcium alginate, gellan gum,carrageenan gum grade iota, kappa or lambda, and medium viscosityhydroxypropylmethyl cellulose.

Medium viscosity sodium carboxymethyl cellulose corresponds to grade ofsodium carboxymethyl cellulose whose viscosity, for a 2% solution inwater at 25° C., is greater than 200 mPa·s and lower than 3100 mPa·s.

Medium viscosity hydroxyethyl cellulose corresponds to a grade ofhydroxyethyl cellulose whose viscosity, for a 2% solution in water at25° C., is greater than 250 mPa·s and lower than 6500 mPa·s. Mediumviscosity hydroxypropylmethyl cellulose corresponds to a grade ofhydroxypropylmethyl cellulose whose viscosity, for a 2% solution inwater at 20° C., is greater than 80 mPa·s. and lower than 3800 mPa·s.

Preferred suspending or viscosifying agents are xanthan gum, especiallyXantural 75™ from Kelco, hydroxyethylcellulose, especially Natrosol250M™ from Ashland, Kappa carrageenan gum, especially Gelcarin PH812™from FMC Biopolymer, and lambda carrageenan gum, especially ViscarinPH209™ from FMC Biopolymer.

In a preferred embodiment, the modified release formulation ofgamma-hydroxybutyrate comprises from 1 to 15% of viscosifying orsuspending agents, preferably from 2 to 10%, more preferably from 2 to5%, and most preferably from 2 to 3% of the formulation.

In a preferred embodiment, the modified release formulation ofgamma-hydroxybutyrate is in the form of a powder that is intended to bedispersed in water prior to administration and further comprises from 1to 15% of a suspending or viscosifying agent selected from a mixture ofxanthan gum, carrageenan gum and hydroxyethylcellulose or xanthan gumand carrageenan gum.

In a preferred embodiment, the modified release formulation ofgamma-hydroxybutyrate is in the form of a powder that is intended to bedispersed in water prior to administration and further comprises: from1.2 to 15% of an acidifying agent selected from malic acid and tartaricacid; and from 1 to 15% of a suspending or viscosifying agent selectedfrom a mixture of xanthan gum, carrageenan gum and hydroxyethylcelluloseor xanthan gum and carrageenan gum.

In a most preferred embodiment, the modified release formulation ofgamma-hydroxybutyrate comprises about 1% of lambda carrageenan gum orViscarin PH209™, about 1% of medium viscosity grade of hydroxyethylcellulose or Natrosol 250M™, and about 0.7% of xanthan gum or Xantural75™. For a 4.5 g dose unit, these percentages will typically equate toabout 50 mg xanthan gum (Xantural 75™), about 75 mg carrageenan gum(Viscarin PH209™) and about 75 mg hydroxyethylcellulose (Natrasol250M™).

Alternative packages of viscosifying or suspending agents, for a 4.5 gdose, include about 50 mg xanthan gum (Xantural 75™) and about 100 mgcarrageenan gum (Gelcarin PH812™), or about 50 mg xanthan gum (Xantural75™), about 75 mg hydroxyethylcellulose (Natrasol 250M™), and about 75mg carrageenan gum (Viscarin PH109™).

In a preferred embodiment, the modified release formulation ofgamma-hydroxybutyrate further comprises a lubricant or a glidant,besides the immediate release and modified release particles ofgamma-hydroxybutyrate. Preferred lubricants and glidants are chosen fromthe group consisting of salts of stearic acid, in particular magnesiumstearate, calcium stearate or zinc stearate, esters of stearic acid, inparticular glyceryl monostearate or glyceryl palmitostearate, stearicacid, glycerol behenate, sodium stearyl fumarate, talc, and colloidalsilicon dioxide.

The preferred lubricant or glidant is magnesium stearate.

The lubricant or glidant can be used in the particulate formulation inan amount of from 0.1 to 5%. The preferred amount is about 0.5%.

Most preferably, the modified release formulation ofgamma-hydroxybutyrate comprises about 0.5% of magnesium stearate.

A preferred modified release formulation of gamma-hydroxybutyratefurther comprises an acidifying agent. The acidifying agent helps toensure that the release profile of the formulation in 0.1N HCl willremain substantially unchanged for at least 15 minutes after mixing,which is approximately the maximum length of time a patient mightrequire before consuming the dose after mixing the formulation with tapwater.

In one particular subembodiment the formulation is a powder, and furthercomprising an acidifying agent and a suspending or viscosifying agent,preferably in the weight percentages recited herein.

The preferred acidifying agents are chosen from the group consisting ofmalic acid, citric acid, tartaric acid, adipic acid, boric acid, maleicacid, phosphoric acid, ascorbic acid, oleic acid, capric acid, caprylicacid, and benzoic acid. In a preferred embodiment, the acidifying agentis present in the formulation from 1.2 to 15%, preferably from 1.2 to10%, preferably from 1.2 to 5%. Preferred acidifying agents are tartaricacid and malic acid, with malic acid being most preferred.

When tartaric acid is employed, it is preferably employed in an amountof from 1 to 10%, from 2.5 to 7.5%, or about 5%. In a most preferredembodiment, the amount of malic acid in the modified release formulationof gamma-hydroxybutyrate is from 1.2 to 15%, preferably from 1.2 to 10%,preferably from 1.2 to 5%, and most preferably 1.6% or 3.2%.

In a most preferred embodiment, the amount of malic acid in the modifiedrelease formulation of gamma hydroxybutyrate is about 1.6%.

The modified release formulation of gamma-hydroxybutyrate preferablyincludes an immediate release portion and a modified release portion ofgamma-hydroxybutyrate, and in a particularly preferred embodiment, theformulation is a particulate formulation that includes a plurality ofimmediate release gamma-hydroxybutyrate particles and a plurality ofmodified release gamma-hydroxybutyrate particles. The molar ratio ofgamma-hydroxybutyrate in the immediate release and modified releaseportions preferably ranges from 0.11:1 to 1.86:1, from 0.17:1 to 1.5:1,from 0.25:1 to 1.22:1, from 0.33:1 to 1.22:1, from 0.42:1 to 1.22:1,from 0.53:1 to 1.22:1, from 0.66:1 to 1.22:1, from 0.66:1 to 1.5:1, from0.8:1 to 1.22:1, and preferably is about 1:1. The molar percentage ofgamma-hydroxybutyrate in the immediate release portion relative to thetotal of gamma-hydroxybutyrate in the formulation preferably ranges from10% to 65%, from 15 to 60%, from 20 to 55%, from 25 to 55%, from 30 to55%, from 35 to 55%, from 40 to 55%, from 40 to 60%, or from 45 to 55%,preferably from 40% to 60%. In a preferred embodiment, the molarpercentage of the gamma-hydroxybutyrate in the immediate release portionrelative to the total of gamma-hydroxybutyrate in the formulation isabout 50%. The molar percentage of gamma-hydroxybutyrate in the modifiedrelease portion relative to the total of gamma-hydroxybutyrate in theformulation preferably ranges from 90% to 35%, from 85 to 40%, from 80to 45%, from 75 to 45%, from 70 to 45%, from 65 to 45%, from 60 to 45%,from 60 to 40%, or from 55 to 45%, preferably from 60% to 40%. In apreferred embodiment, the molar ratio of the gamma-hydroxybutyrate inthe modified release portion relative to the total ofgamma-hydroxybutyrate in the formulation is about 50%. The weightpercentage of the IR microparticles relative to the total weight of IRmicroparticles and MR microparticles, preferably ranges from 7.2% to58.2%, from 11.0% to 52.9%, from 14.9% to 47.8%, from 18.9% to 47.8%,from 23.1% to 47.8%, from 27.4% to 47.8%, from 31.8% to 47.8%, from31.8% to 52.9%, or from 36.4% to 47.8%. In other embodiments, the weightpercentage of the IR microparticles relative to the total weight of IRmicroparticles and MR microparticles preferably ranges from 5.9% to63.2%, from 9.1% to 58.1%, from 12.4% to 53.1%, from 19.9% to 53.1%,from 19.6% to 53.1%, from 23.4% to 53.1%, from 27.4% to 53.1% from 27.4%to 58.1%, preferably from 31.7% to 53.1%.

In a preferred embodiment, the finished formulation comprises 50% of itssodium oxybate content in immediate-release particles consisting of80.75% w/w of sodium oxybate, 4.25% w/w of Povidone K30 and 15% ofmicrocrystalline cellulose spheres with a volume mean diameter of about95 microns to 450 microns and 50% of its sodium oxybate content inmodified release particles consisting of 10.5% w/w of microcrystallinecellulose spheres with a volume mean diameter of about 95 microns toabout 450 microns, layered with 56.5% w/w of sodium oxybate mixed with3% w/w of Povidone™ K30 and finally coated with a coating compositionconsisting of 18% w/w of hydrogenated vegetable oil (Lubritab™ orequivalent), 4% of methacrylic acid copolymer type C (Eudragit™ L100-55or equivalent) and 8% of methacrylic acid copolymer type B (Eudragit™S100 or equivalent).

In a preferred embodiment, the finished formulation comprises 50% of itssodium oxybate content in immediate-release particles consisting of80.75% w/w of sodium oxybate, 4.25% w/w of Povidone K30 and 15% ofmicrocrystalline cellulose spheres with a volume mean diameter of about95 microns to 170 microns and 50% of its sodium oxybate content inmodified release particles consisting of 10.5% w/w of microcrystallinecellulose spheres with a volume mean diameter of about 95 microns toabout 170 microns, layered with 56.5% w/w of sodium oxybate mixed with3% w/w of Povidone™ K30 and finally coated with a coating compositionconsisting of 18% w/w of hydrogenated vegetable oil (Lubritab™ orequivalent), 4% of methacrylic acid copolymer type C (Eudragit™ L100-55or equivalent) and 8% of methacrylic acid copolymer type B (Eudragit™S100 or equivalent).

In a preferred embodiment, the finished formulation comprises 50% of itssodium oxybate content in immediate-release particles consisting of80.75% w/w of sodium oxybate, 4.25% w/w of Povidone K30 and 15% ofmicrocrystalline cellulose spheres with a volume mean diameter of about95 microns to about 450 microns and 50% of its sodium oxybate content inmodified release particles consisting of 11.3% w/w of microcrystallinecellulose spheres with a volume mean diameter of about 95 microns toabout 450 microns, layered with 60.5% w/w of sodium oxybate mixed with3.2% w/w of Povidone™ K30 and finally coated with a coating compositionconsisting of 15% w/w of hydrogenated vegetable oil (Lubritab™ orequivalent), 0.75% of methacrylic acid copolymer type C (Eudragit™L100-55 or equivalent) and 9.25% of methacrylic acid copolymer type B(Eudragit™ S100 or equivalent).

In a preferred embodiment, the finished formulation comprises 50% of itssodium oxybate content in immediate-release particles consisting of80.75% w/w of sodium oxybate, 4.25% w/w of Povidone™ K30 and 15% ofmicrocrystalline cellulose spheres with a volume mean diameter of about95 microns to about 170 microns and 50% of its sodium oxybate content inmodified release particles consisting of 11.3% w/w of microcrystallinecellulose spheres with a volume mean diameter of about 95 microns toabout 170 microns, layered with 60.5% w/w of sodium oxybate mixed with3.2% w/w of Povidone™ K30 and finally coated with a coating compositionconsisting of 15% w/w of hydrogenated vegetable oil (Lubritab™ orequivalent), 0.75% of methacrylic acid copolymer type C (Eudragit™L100-55 or equivalent) and 9.25% of methacrylic acid copolymer type B(Eudragit™ S100 or equivalent).

In a preferred embodiment, the finished formulation comprises 50% of itsgamma-hydroxybutyrate content in immediate-release particles consistingof 80.75% w/w of potassium salt of gamma-hydroxybutyric acid, 4.25% w/wof Povidone K30 and 15% of microcrystalline cellulose spheres with avolume mean diameter of about 95 microns to about 450 microns and 50% ofits gamma-hydroxybutyrate content in modified release particlesconsisting of 10.5% w/w of microcrystalline cellulose spheres with avolume mean diameter of about 95 microns to about 450 microns, layeredwith 56.5% w/w of sodium oxybate mixed with 3% w/w of Povidone™ K30 andfinally coated with a coating composition consisting of 18% w/w ofhydrogenated vegetable oil (Lubritab™ or equivalent), 4% of methacrylicacid copolymer type C (Eudragit™ L100-55 or equivalent) and 8% ofmethacrylic acid copolymer type B (Eudragit™ S100 or equivalent).

In a preferred embodiment, the finished formulation comprises 50% of itsgamma-hydroxybutyrate content in immediate-release particles consistingof 80.75% w/w of potassium salt of gamma-hydroxybutyric acid, 4.25% w/wof Povidone K30 and 15% of microcrystalline cellulose spheres with avolume mean diameter of about 95 microns to about 170 microns and 50% ofits gamma-hydroxybutyrate content in modified release particlesconsisting of 10.5% w/w of microcrystalline cellulose spheres with avolume mean diameter of about 95 microns to about 170 microns, layeredwith 56.5% w/w of sodium oxybate mixed with 3% w/w of Povidone™ K30 andfinally coated with a coating composition consisting of 18% w/w ofhydrogenated vegetable oil (Lubritab™ or equivalent), 4% of methacrylicacid copolymer type C (Eudragit™ L100-55 or equivalent) and 8% ofmethacrylic acid copolymer type B (Eudragit™ S100 or equivalent).

In a preferred embodiment, the finished formulation comprises 16.7% ofits gamma-hydroxybutyrate content in immediate-release particlesconsisting of 80.75% w/w of potassium salt of gamma-hydroxybutyric acid,4.25% w/w of Povidone K30 and 15% of microcrystalline cellulose sphereswith a volume mean diameter of about 95 microns to about 450 microns,16.7% of its gamma-hydroxybutyrate content in immediate-releaseparticles consisting of 80.75% w/w of magnesium salt ofgamma-hydroxybutyric acid, 4.25% w/w of Povidone K30 and 15% ofmicrocrystalline cellulose spheres with a volume mean diameter of about95 microns to about 450 microns, 16.7% of its gamma-hydroxybutyratecontent in immediate-release particles consisting of 80.75% w/w ofcalcium salt of gamma-hydroxybutyric acid, 4.25% w/w of Povidone K30 and15% of microcrystalline cellulose spheres with a volume mean diameter ofabout 95 microns to about 450 microns and 50% of itsgamma-hydroxybutyrate content in modified release particles consistingof 10.5% w/w of microcrystalline cellulose spheres with a volume meandiameter of about 95 microns to about 450 microns, layered with 56.5%w/w of sodium oxybate mixed with 3% w/w of Povidone™ K30 and finallycoated with a coating composition consisting of 18% w/w of hydrogenatedvegetable oil (Lubritab™ or equivalent), 4% of methacrylic acidcopolymer type C (Eudragit™ L100-55 or equivalent) and 8% of methacrylicacid copolymer type B (Eudragit™ S100 or equivalent).

In a preferred embodiment, the finished formulation comprises 16.7% ofits gamma-hydroxybutyrate content in immediate-release particlesconsisting of 80.75% w/w of potassium salt of gamma-hydroxybutyric acid,4.25% w/w of Povidone K30 and 15% of microcrystalline cellulose sphereswith a volume mean diameter of about 95 microns to about 170 microns,16.7% of its gamma-hydroxybutyrate content in immediate-releaseparticles consisting of 80.75% w/w of magnesium salt ofgamma-hydroxybutyric acid, 4.25% w/w of Povidone K30 and 15% ofmicrocrystalline cellulose spheres with a volume mean diameter of about95 microns to about 170 microns, 16.7% of its gamma-hydroxybutyratecontent in immediate-release particles consisting of 80.75% w/w ofcalcium salt of gamma-hydroxybutyric acid, 4.25% w/w of Povidone K30 and15% of microcrystalline cellulose spheres with a volume mean diameter ofabout 95 microns to about 170 microns and 50% of itsgamma-hydroxybutyrate content in modified release particles consistingof 10.5% w/w of microcrystalline cellulose spheres with a volume meandiameter of about 95 microns to about 170 microns, layered with 56.5%w/w of sodium oxybate mixed with 3% w/w of Povidone™ K30 and finallycoated with a coating composition consisting of 18% w/w of hydrogenatedvegetable oil (Lubritab™ or equivalent), 4% of methacrylic acidcopolymer type C (Eudragit™ L100-55 or equivalent) and 8% of methacrylicacid copolymer type B (Eudragit™ S100 or equivalent).

In a preferred embodiment, the finished formulation comprises 50% of itsgamma-hydroxybutyrate content in immediate-release particles consistingof 80.75% w/w of potassium salt of gamma-hydroxybutyric acid, 4.25% w/wof Povidone K30 and 15% of microcrystalline cellulose spheres with avolume mean diameter of about 95 microns to about 450 microns and 50% ofits gamma-hydroxybutyrate content in modified release particlesconsisting of 10.5% w/w of microcrystalline cellulose spheres with avolume mean diameter of about 95 microns to about 450 microns, layeredwith 56.5% w/w of calcium salt of gamma-hydroxybutyric acid mixed with3% w/w of Povidone™ K30 and finally coated with a coating compositionconsisting of 18% w/w of hydrogenated vegetable oil (Lubritab™ orequivalent), 4% of methacrylic acid copolymer type C (Eudragit™ L100-55or equivalent) and 8% of methacrylic acid copolymer type B (Eudragit™S100 or equivalent).

In a preferred embodiment, the finished formulation comprises 50% of itsgamma-hydroxybutyrate content in immediate-release particles consistingof 80.75% w/w of potassium salt of gamma-hydroxybutyric acid, 4.25% w/wof Povidone K30 and 15% of microcrystalline cellulose spheres with avolume mean diameter of about 95 microns to about 170 microns and 50% ofits gamma-hydroxybutyrate content in modified release particlesconsisting of 10.5% w/w of microcrystalline cellulose spheres with avolume mean diameter of about 95 microns to about 170 microns, layeredwith 56.5% w/w of calcium salt of gamma-hydroxybutyric acid mixed with3% w/w of Povidone™ K30 and finally coated with a coating compositionconsisting of 18% w/w of hydrogenated vegetable oil (Lubritab™ orequivalent), 4% of methacrylic acid copolymer type C (Eudragit™ L100-55or equivalent) and 8% of methacrylic acid copolymer type B (Eudragit™S100 or equivalent).

Other Characteristics of Immediate Release Portion

The immediate release portion of the formulation can take any formcapable of achieving an immediate release of the gamma-hydroxybutyratewhen ingested. For example, when the formulation is a particulateformulation, the formulation can include unmodified “raw”gamma-hydroxybutyrate, rapidly dissolving gamma-hydroxybutyrategranules, particles or microparticles comprised of a core covered by agamma-hydroxybutyrate loaded layer containing a binder such as povidone.

The IR granules or particles of gamma-hydroxybutyrate can be made usingany manufacturing process suitable to produce the required particles,including:

-   -   agglomeration of the gamma-hydroxybutyrate sprayed preferably in        the molten state, such as the Glatt ProCell™ technique,    -   extrusion and spheronization of the gamma-hydroxybutyrate,        optionally with one or more physiologically acceptable        excipients,    -   wet granulation of the gamma-hydroxybutyrate, optionally with        one or more physiologically acceptable excipients,    -   compacting of the gamma-hydroxybutyrate, optionally with one or        more physiologically acceptable excipients,    -   granulation and spheronization of the gamma-hydroxybutyrate,        optionally with one or more physiologically acceptable        excipients, the spheronization being carried out for example in        a fluidized bed apparatus equipped with a rotor, in particular        using the Glatt CPS™ technique,    -   spraying of the gamma-hydroxybutyrate, optionally with one or        more physiologically acceptable excipients, for example in a        fluidized bed type apparatus equipped with zig-zag filter, in        particular using the Glatt MicroPx™ technique, or    -   spraying, for example in a fluidized bed apparatus optionally        equipped with a partition tube or Wurster tube, the        gamma-hydroxybutyrate, optionally with one or more        physiologically acceptable excipients, in dispersion or in        solution in an aqueous or organic solvent on a core.

Preferably, the immediate release portion of the formulation is in theform of microparticles comprising the immediate releasegamma-hydroxybutyrate and optional pharmaceutically acceptableexcipients. In a preferred embodiment, the immediate releasemicroparticles of gamma-hydroxybutyrate have a volume mean diameterD(4,3) of from 10 to 1000 microns, preferably from 95 to 600 microns,more preferably from 150 to 400 microns. Most preferably their volumemean diameter is about 270 microns.

The preferred immediate release particles of gamma-hydroxybutyrate ofthe present invention comprises a core and a layer deposited on the corethat contains the gamma-hydroxybutyrate. The core can be any particlechosen from the group consisting of:

-   -   crystals or spheres of lactose, sucrose (such as Compressuc™ PS        from Tereos), microcrystalline cellulose (such as Avicel™ from        FMC Biopolymer, Cellet™ from Pharmatrans or Celphere™ from Asahi        Kasei), sodium chloride, calcium carbonate (such as Omyapure™ 35        from Omya), sodium hydrogen carbonate, dicalcium phosphate (such        as Dicafos™ AC 92-12 from Budenheim) or tricalcium phosphate        (such as Tricafos™ SC93-15 from Budenheim);    -   composite spheres or granules, for example sugar spheres        comprising sucrose and starch (such as Suglets™ from NP Pharm),        spheres of calcium carbonate and starch (such as Destab™ 90 S        Ultra 250 from Particle Dynamics) or spheres of calcium        carbonate and maltodextrin (such as Hubercal™ CCG4100        fromHuber).

The core can also comprise other particles of pharmaceuticallyacceptable excipients such as particles of hydroxypropyl cellulose (suchas Klucel™ from Aqualon Hercules), guar gum particles (such as Grinsted™Guar from Danisco), xanthan particles (such as Xantural™ 180 from CPKelco).

According to a particular embodiment of the invention, the cores aresugar spheres or microcrystalline cellulose spheres, such as Cellets™90, Cellets™ 100 or Cellets™ 127 marketed by Pharmatrans, or alsoCelphere™ CP 203, Celphere™ CP305, Celphere™ SCP 100. Preferably thecore is a microcrystalline cellulose sphere. Most preferably the core isa Cellets™ 127 from Pharmatrans.

The core preferably has a mean volume diameter of about 95 to about 450microns, preferably about 95 to about 170 microns, most preferably about140 microns.

The layer deposited onto the core comprises the immediate releasegamma-hydroxybutyrate. Preferably the layer also comprises a binder,which can be chosen from the group consisting of:

-   -   low molecular weight hydroxypropyl cellulose (such as Klucel™ EF        from Aqualon-Hercules), low molecular weight hydroxypropyl        methylcellulose (or hypromellose) (such as Methocel™ E3 or E5        from Dow), or low molecular weight methylcellulose (such as        Methocel™ A15 from Dow);    -   low molecular weight polyvinyl pyrrolidone (or povidone) (such        as Plasdone™ K29/32 from ISP or Kollidon™ 30 from BASF), vinyl        pyrrolidone and vinyl acetate copolymer (or copovidone) (such as        Plasdone™: S630 from ISP or Kollidon™ VA 64 from BASF);    -   dextrose, pregelatinized starch, maltodextrin; and mixtures        thereof.

Low molecular weight hydroxypropyl cellulose corresponds to grades ofhydroxypropyl cellulose having a molecular weight of less than 800,000g/mol, preferably less than or equal to 400,000 g/mol, and in particularless than or equal to 100,000 g/mol. Low molecular weight hydroxypropylmethylcellulose (or hypromellose) corresponds to grades of hydroxypropylmethylcellulose the solution viscosity of which, for a 2% solution inwater and at 20° C., is less than or equal to 1,000 mPa·s, preferablyless than or equal to 100 mPa·s and in particular less than or equal to15 mPa·s. Low molecular weight polyvinyl pyrrolidone (or povidone)corresponds to grades of polyvinyl pyrrolidone having a molecular weightof less than or equal to 1,000,000 g/mol, preferably less than or equalto 800,000 g/mol, and in particular less than or equal to 100,000 g/mol.

Preferably, the binding agent is chosen from low molecular weightpolyvinylpyrrolidone or povidone (for example, Plasdone™ K29/32 fromISP), low molecular weight hydroxypropyl cellulose (for example, Klucel™EF from Aqualon-Hercules), low molecular weight hydroxypropylmethylcellulose or hypromellose (for example, Methocel™ E3 or E5 fromDow) and mixtures thereof.

The preferred binder is povidone K30 or K29/32, especially Plasdone™K29/32 from ISP. The binder can be present in an amount of 0 to 80%, 0to 70%, 0 to 60%, 0 to 50%, 0 to 40%, 0 to 30%, 0 to 25%, 0 to 20%, 0 to15%, 0 to 10%, or from 1 to 9%, most preferably 5% of binder based onthe total weight of the immediate release coating.

The preferred amount of binder is 5% of binder over the total mass ofgamma-hydroxybutyrate and binder.

The layer deposited on the core can represent at least 10% by weight,and even greater than 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75,80, 85 or 90% by weight of the total weight of the immediate releaseparticle of gamma-hydroxybutyrate. Most preferably, the layer depositedon the core represents about 85% of the weight of the immediate releaseparticle of gamma-hydroxybutyrate.

According to a preferred embodiment, the immediate-release particlescomprise 80.75% w/w of gamma-hydroxybutyrate, 4.25% w/w of Povidone K30and 15% of microcrystalline cellulose spheres.

According to a preferred embodiment, the immediate-release particlescomprise 80.75% w/w of gamma-hydroxybutyrate, 4.25% w/w of Povidone K30and 15% of microcrystalline cellulose spheres with a volume meandiameter of about 95 microns to about 450 microns.

According to a preferred embodiment, the immediate-release particlescomprise 80.75% w/w of gamma-hydroxybutyrate, 4.25% w/w of Povidone K30and 15% of microcrystalline cellulose spheres with a volume meandiameter of about 95 microns to about 170 microns.

According to a preferred embodiment, the immediate-release particlescomprise 80.75% w/w of sodium oxybate, 4.25% w/w of Povidone K30 and 15%of microcrystalline cellulose spheres.

According to another preferred embodiment, the immediate-releaseparticles comprise 80.75% w/w of potassium salt of gamma-hydroxybutyricacid, 4.25% w/w of Povidone K30 and 15% of microcrystalline cellulosespheres.

According to another preferred embodiment, the immediate-releaseparticles comprise 80.75% w/w of calcium salt of gamma-hydroxybutyricacid, 4.25% w/w of Povidone K30 and 15% of microcrystalline cellulosespheres.

According to another preferred embodiment, the immediate-releaseparticles comprise 80.75% w/w of magnesium salt of gamma-hydroxybutyricacid, 4.25% w/w of Povidone K30 and 15% of microcrystalline cellulosespheres.

According to another embodiment, the immediate-release particles aremanufactured by dissolving the gamma-hydroxybutyrate and the PovidoneK30 in a mixture of water/ethanol 40/60 w/w and spraying the resultingsolution onto the surface of the microcrystalline cellulose spheres.

Other Characteristics of Modified Release Portion

The modified release portion can be any formulation that provides thedesired in vitro dissolution profile of gamma-hydroxybutyrate. Themodified release portion is preferably comprised of modified releaseparticles, obtained by coating immediate release particles ofgamma-hydroxybutyrate with a coating (or coating film) that inhibits theimmediate release of the gamma-hydroxybutyrate. In one sub-embodimentthe modified release portion comprises particles comprising: (a) aninert core; (b) a coating; and (c) a layer comprising the gammahydroxybutyrate interposed between the core and the coating.

In a preferred embodiment, the modified release portion comprises atime-dependent release mechanism and a pH-dependent release mechanism.

In a preferred embodiment, the coating film comprises at least onepolymer carrying free carboxylic groups, and at least one hydrophobiccompound preferably characterized by a melting point equal or greaterthan 40° C.

The polymer carrying free carboxylic groups is preferably selected from:(meth)acrylic acid/alkyl (meth)acrylate copolymers or methacrylic acidand methylmethacrylate copolymers or methacrylic acid and ethyl acrylatecopolymers or methacrylic acid copolymers type A, B or C, cellulosederivatives carrying free carboxylic groups, preferably celluloseacetate phthalate, cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, carboxymethylethyl cellulose, cellulose acetatetrimellitate, hydroxypropyl methyl cellulose acetate succinate,polyvinyl acetate phthalate, zein, shellac, alginate and mixturesthereof.

In a preferred embodiment, the methacrylic acid copolymers are chosenfrom the group consisting of poly (methacrylic acid, methylmethacrylate) 1:1 or Eudragit™ L100 or equivalent, poly (methacrylicacid, ethyl acrylate) 1:1 or Eudragit™ L100-55 or equivalent and poly(methacrylic acid, methyl methacrylate) 1:2 or Eudragit™ S100 orequivalent.

In another subembodiment the coating comprises a polymer carrying freecarboxylic groups wherein the free carboxylic groups are substantiallyionized at pH 7.5.

The hydrophobic compound with a melting point equal or greater than 40°C. can be selected from the group consisting of hydrogenated vegetableoils, vegetable waxes, wax yellow, wax white, wax microcrystalline,lanolin, anhydrous milk fat, hard fat suppository base, lauroyl macrogolglycerides, polyglyceryl diisostearate, diesters or triesters ofglycerol with a fatty acid, and mixtures thereof.

Even more preferably, the hydrophobic compound with a melting pointequal or greater than 40° C. is chosen from the group of followingproducts: hydrogenated cottonseed oil, hydrogenated soybean oil,hydrogenated palm oil, glyceryl behenate, hydrogenated castor oil,candellila wax, tristearin, tripalmitin, trimyristin, yellow wax, hardfat or fat that is useful as suppository bases, anhydrous dairy fats,lanolin, glyceryl palmitostearate, glyceryl stearate, lauryl macrogolglycerides, polyglyceryl diisostearate, diethylene glycol monostearate,ethylene glycol monostearate, omega 3 fatty acids, and mixtures thereof.A particularly preferred subgroup of products comprises hydrogenatedcottonseed oil, hydrogenated soybean oil, hydrogenated palm oil,glyceryl behenate, hydrogenated castor oil, candelilla wax, tristearin,tripalmitin, trimyristin, beeswax, hydrogenated poly-1 decene, carnaubawax, and mixtures thereof.

In practice, and without this being limiting, it is preferable thehydrophobic compound with a melting point equal or greater than 40° C.to be chosen from the group of products sold under the followingtrademarks: Dynasan™, Cutina™, Hydrobase™, Dub™, Castorwax™, Croduret™,Compritol™, Sterotex™, Lubritab™, Apifil™, Akofine™, Softisan™,Hydrocote™, Livopol™, Super Hartolan™, MGLA™, Corona™, Protalan™Akosoft™, Akosol™, Cremao™, Massupol™, Novata™, Suppocire™, Wecobee™Witepsol™, Lanolin™, Incromega™, Estaram™, Suppoweiss™, Gelucire™,Precirol™, Emulcire™, Plurol diisostéarique™, Geleol™, Hydrine™,Monthyle™, Kahlwax™ and mixtures thereof; and, preferably, from thegroup of products sold under the following trademarks: Dynasan™P60,Dynasan™114, Dynasan™116, Dynasan™118, Cutina™ HR, Hydrobase™ 66-68,Dub™ HPH, Compritol™ 888, Sterotex™ NF, Sterotex™ K, Lubritab™, andmixtures thereof.

A particularly suitable coating is composed of a mixture of hydrogenatedvegetable oil and a methacrylic acid copolymer. The exact structure andamount of each component, and the amount of coating applied to theparticle, controls the release rate and release triggers. Eudragit®methacrylic acid copolymers, namely the methacrylic acid-methylmethacrylate copolymers and the methacrylic acid-ethyl acrylatecopolymers, have a pH-dependent solubility: typically, the pH triggeringthe release of the active ingredient from the microparticles is set bythe choice and mixture of appropriate Eudragit® polymers. In the case ofgamma hydroxybutyrate modified release microparticles, the theoreticalpH triggering the release is preferably from 5.5 to 6.97 or 6.9, morepreferably 6.5 up to 6.9. By “pH trigger” is meant the minimum pH abovewhich dissolution of the polymer occurs.

In a particular embodiment, the coating comprises a hydrophobic compoundwith a melting point equal or greater than 40° C. and a polymer carryingfree carboxylic groups are present in a weight ratio from 0.4 or 0.5 to4, preferably from 0.6 or 0.67 to 2.5, most preferably from 0.6 or 0.67to 2.33; most preferably about 1.5.

A particularly suitable coating is composed of a mixture of hydrogenatedvegetable oil and a methacrylic acid copolymer with a theoretical pHtriggering the release from 6.5 up to 6.97 in a weight ratio from 0.4 or0.5 to 4, preferably from 0.6 or 0.67 to 2.5, most preferably from 0.6or 0.67 to 2.33; most preferably of about 1.5.

The modified release particles of gamma-hydroxybutyrate preferably havea volume mean diameter of from 100 to 1200 microns, from 100 to 500microns, from 200 to 800 microns, and preferably of about 320 microns.

The coating can preferably represent 10 to 50%, 15 to 45%, 20 to 40%, or25 to 35% by weight of the total weight of the coated modified releaseparticles. Preferably, the coating represents 25-30% by weight of thetotal weight of the modified release particles of gamma-hydroxybutyrate.

In a preferred embodiment, the coating layer of the modified releaseparticles of gamma-hydroxybutyrate is obtained by spraying, inparticular in a fluidized bed apparatus, a solution, suspension ordispersion comprising the coating composition as defined previously ontothe immediate release particles of gamma-hydroxybutyrate, in particularthe immediate release particles of gamma-hydroxybutyrate as previouslydescribed. Preferably, the coating is formed by spraying in a fluidizedbed equipped with a Wurster or partition tube and according to an upwardspray orientation or bottom spray a solution of the coating excipientsin hot isopropyl alcohol.

According to a preferred embodiment, the modified release particles ofgamma-hydroxybutyrate consist of 10.5% w/w of microcrystalline cellulosespheres with a volume mean diameter of about 95 microns to about 450microns, layered with 56.5% w/w of gamma-hydroxybutyrate mixed with 3%w/w of Povidone™ K30 and finally coated with a coating compositionconsisting of 18% w/w of hydrogenated vegetable oil (Lubritab™ orequivalent), 4% of methacrylic acid copolymer type C (Eudragit™ L100-55or equivalent) and 8% of methacrylic acid copolymer type B (Eudragit™S100 or equivalent), all percentages expressed based on the total weightof the final modified release particles of gamma-hydroxybutyrate.

According to a preferred embodiment, the modified release particles ofgamma-hydroxybutyrate consist of 10.5% w/w of microcrystalline cellulosespheres with a volume mean diameter of about 95 microns to about 170microns, layered with 56.5% w/w of gamma-hydroxybutyrate mixed with 3%w/w of Povidone™ K30 and finally coated with a coating compositionconsisting of 18% w/w of hydrogenated vegetable oil (Lubritab™ orequivalent), 4% of methacrylic acid copolymer type C (Eudragit™ L100-55or equivalent) and 8% of methacrylic acid copolymer type B (Eudragit™S100 or equivalent), all percentages expressed based on the total weightof the final modified release particles of gamma-hydroxybutyrate.

According to a preferred embodiment, the modified release particles ofgamma-hydroxybutyrate consist of 10.5% w/w of microcrystalline cellulosespheres with a volume mean diameter of about 95 microns to about 450microns, layered with 56.5% w/w of sodium oxybate mixed with 3% w/w ofPovidone™ K30 and finally coated with a coating composition consistingof 18% w/w of hydrogenated vegetable oil (Lubritab™ or equivalent), 4%of methacrylic acid copolymer type C (Eudragit™ L100-55 or equivalent)and 8% of methacrylic acid copolymer type B (Eudragit™ S100 orequivalent), all percentages expressed based on the total weight of thefinal modified release particles of sodium oxybate.

According to a preferred embodiment, the modified release particles ofgamma-hydroxybutyrate consist of 10.5% w/w of microcrystalline cellulosespheres with a volume mean diameter of about 95 microns to about 170microns, layered with 56.5% w/w of sodium oxybate mixed with 3% w/w ofPovidone™ K30 and finally coated with a coating composition consistingof 18% w/w of hydrogenated vegetable oil (Lubritab™ or equivalent), 4%of methacrylic acid copolymer type C (Eudragit™ L100-55 or equivalent)and 8% of methacrylic acid copolymer type B (Eudragit™ S100 orequivalent), all percentages expressed based on the total weight of thefinal modified release particles of sodium oxybate.

According to another preferred embodiment, the modified releaseparticles of gamma-hydroxybutyrate consist of 11.3% w/w ofmicrocrystalline cellulose spheres with a volume mean diameter of about95 microns to about 450 microns, layered with 60.5% w/w ofgamma-hydroxybutyrate mixed with 3.2% w/w of Povidone™ K30 and finallycoated with a coating composition consisting of 15% w/w of hydrogenatedvegetable oil (Lubritab™ or equivalent), 0.75% of methacrylic acidcopolymer type C (Eudragit™ L100-55 or equivalent) and 9.25% ofmethacrylic acid copolymer type B (Eudragit™ S100 or equivalent).

According to another preferred embodiment, the modified releaseparticles of gamma-hydroxybutyrate consist of 11.3% w/w ofmicrocrystalline cellulose spheres with a volume mean diameter of about95 microns to about 170 microns, layered with 60.5% w/w ofgamma-hydroxybutyrate mixed with 3.2% w/w of Povidone™ K30 and finallycoated with a coating composition consisting of 15% w/w of hydrogenatedvegetable oil (Lubritab™ or equivalent), 0.75% of methacrylic acidcopolymer type C (Eudragit™ L100-55 or equivalent) and 9.25% ofmethacrylic acid copolymer type B (Eudragit™ S100 or equivalent).

According to another preferred embodiment, the modified releaseparticles of gamma-hydroxybutyrate consist of 11.3% w/w ofmicrocrystalline cellulose spheres with a volume mean diameter of about95 microns to about 450 microns, layered with 60.5% w/w of sodiumoxybate mixed with 3.2% w/w of Povidone™ K30 and finally coated with acoating composition consisting of 15% w/w of hydrogenated vegetable oil(Lubritab™ or equivalent), 0.75% of methacrylic acid copolymer type C(Eudragit™ L100-55 or equivalent) and 9.25% of methacrylic acidcopolymer type B (Eudragit™ S100 or equivalent).

According to another preferred embodiment, the modified releaseparticles of gamma-hydroxybutyrate consist of 11.3% w/w ofmicrocrystalline cellulose spheres with a volume mean diameter of about95 microns to about 170 microns, layered with 60.5% w/w of sodiumoxybate mixed with 3.2% w/w of Povidone™ K30 and finally coated with acoating composition consisting of 15% w/w of hydrogenated vegetable oil(Lubritab™ or equivalent), 0.75% of methacrylic acid copolymer type C(Eudragit™ L100-55 or equivalent) and 9.25% of methacrylic acidcopolymer type B (Eudragit™ S100 or equivalent).

Packaging

The modified release formulation of gamma-hydroxybutyrate is preferablysupplied in sachets or stick-packs comprising a particulate formulation.The sachets are preferably available in several different doses,comprising gamma-hydroxybutyrate in amounts equivalents to 0.5 g, 1.0 g,1.5 g, 3.0 g, 4.5 g, 6.0 g, 7.5 g, 9.0 g, 10.5 g and/or 12 g of sodiumoxybate. Depending on the dose required, one or more of these sachetscan be opened, and its contents mixed with tap water to provide thenightly dose of gamma-hydroxybutyrate.

Methods of Treatment

The invention further provides a method of treating a disorder treatablewith gamma-hydroxybutyrate in a human subject in need thereof comprisingorally administering a single bedtime daily dose to said human amountsof gamma-hydroxybutyrate equivalent to from 3.0 to 12.0 g of sodiumoxybate in the formulation of the present invention. The inventionfurther provides methods of treating narcolepsy, types 1 and/or 2, byorally administering at bedtime a therapeutically effective amount of agamma-hydroxybutyrate formulation characterized by the novelgamma-hydroxybutyrate pharmacokinetics or dissolution properties of thepresent invention. The modified release formulation of the presentinvention is effective to treat narcolepsy Type 1 or Type 2, whereinsaid treatment of narcolepsy is defined as reducing excessive daytimesleepiness or reducing the frequency of cataplectic attacks. Thetherapeutically effective amount preferably comprises equivalents from3.0 to 12.0 g of sodium oxybate, more preferably from to 9.0 g of sodiumoxybate, and most preferably 4.5, 6.0, 7.5 or 9.0 g of sodium oxybate.The effectiveness of the treatment can be measured by one or anycombination of the following criteria:

-   -   Increase the mean sleep latency, preferably as determined on the        Maintenance of Wakefulness Test (MWT)    -   Improve the Clinical Global Impression (CGI) rating of        sleepiness    -   Decrease the number of cataplexy attacks (NCA) preferably        determined from the cataplexy frequency item in the Sleep and        Symptoms Daily Diary    -   Decrease the disturbed nocturnal sleep (DNS), the disturbed        nocturnal events or the adverse respiratory events preferably as        determined by polysomnographic (PSG) measures of sleep        fragmentation    -   Decrease the excessive daytime sleepiness (EDS) preferably as        measured by patient report via the Epworth Sleepiness Scale        (ESS)    -   Decrease the daytime sleepiness as measured by the Maintenance        of Wakefulness Test based on EEG measures of wakefulness    -   Decrease PSG transitions from N/2 to N/3 and REM sleep to wake        and N1 sleep (as determined by C Iber, S Ancoli-Israel, A        Chesson, S F Quan. The AASM Manual for the Scoring of Sleep and        Associated Events. Westchester, Ill.: American Academy of Sleep        Medicine; 2007).    -   Decrease the number of arousals or wakenings, preferably        obtained from a PSG as defined by the American Academy of Sleep        Medicine    -   Improve the sleep quality, preferably obtained from one or more        of (i) the Sleep and Symptom Daily Diary, (ii) Visual Analog        Scale (VAS) for sleep quality and sleep diary, and (iii) VAS for        the refreshing nature of sleep    -   Decrease the Hypnagogic Hallucinations (HH) or sleep paralysis        (SP) symptoms in NT1 narcolepsy patients, preferably as measured        by the Sleep and Symptom Daily Diary

In a preferred embodiment, the treatment of the present invention issuperior, as measured by any one or combination of the foregoingcriteria, to an equal dose administered twice nightly of an immediaterelease liquid solution of sodium oxybate, with the second doseadministered 4 hours after the first dose.

The invention further provides a method of treatment of narcolepsy Type1 or Type 2 wherein, compared to a dosing regimen consisting ofadministering half the dose at t₀ and another half of the dose at t_(4h)of an immediate release liquid solution of sodium oxybate, a singlebedtime daily dose administration of a therapeutically effective amountof the formulation of the invention has been shown to produce lessconfusion, less depressive syndrome, less incontinence, less nausea orless sleepwalking.

Additional Embodiments

In one additional embodiment, the invention provides a modified releaseformulation of gamma-hydroxybutyrate, preferably comprising immediaterelease and modified release portions, wherein the formulation releases(a) at least 80% of its gamma-hydroxybutyrate at 1 hour when tested in adissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.05Mmonobasic potassium phosphate buffer pH 6.8 at a temperature of 37° C.and a paddle speed of 75 rpm, and (b) from 10% to 65%, of itsgamma-hydroxybutyrate at one hour and three hours when tested in adissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1Nhydrochloric acid at a temperature of 37° C. and a paddle speed of 75rpm.

In a second additional embodiment, the invention provides a modifiedrelease formulation of gamma-hydroxybutyrate, comprising immediaterelease and modified release portions, wherein (a) the formulationreleases at least 80% of its gamma-hydroxybutyrate at 1 hour when testedin a dissolution apparatus 2 according to USP 38 <711> in 900 mL of0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of37° C. and a paddle speed of 75 rpm, (b) the formulation releases from10% to 65% of its gamma-hydroxybutyrate at one hour and three hours whentested in a dissolution apparatus 2 according to USP 38 <711> in 900 mLof 0.1N hydrochloric acid at a temperature of 37° C. and a paddle speedof 75 rpm, and (c) the modified release portion releases greater than80% of its gamma-hydroxybutyrate at 3 hours in a dissolution teststarted in 750 mL of 0.1N hydrochloric acid for 2 hours then switched to950 mL 0.05M monobasic potassium phosphate buffer adjusted to pH 6.8 ata temperature of 37° C. and a paddle speed of 75 rpm.

In a third additional embodiment, the invention provides a modifiedrelease formulation of gamma-hydroxybutyrate, comprising immediaterelease and modified release portions, wherein (a) the formulationreleases at least 80% of its gamma-hydroxybutyrate at 1 hour when testedin a dissolution apparatus 2 according to USP 38 <711> in 900 mL of0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of37° C. and a paddle speed of 75 rpm, (b) the formulation releases 10% to65%, of its gamma-hydroxybutyrate at one hour and at three hours whentested in a dissolution apparatus 2 according to USP 38 <711> in 900 mLof 0.1N hydrochloric acid at a temperature of 37° C. and a paddle speedof 75 rpm, (c) the formulation releases greater than 60% of itsgamma-hydroxybutyrate at 10 hours when tested in a dissolution apparatus2 according to USP 38 <711> in 900 mL of 0.1N hydrochloric acid at atemperature of 37° C. and a paddle speed of 75 rpm, and (d) the modifiedrelease portion releases greater than 80% of its gamma-hydroxybutyrateat 3 hours in a dissolution test started in 750 mL of 0.1N hydrochloricacid for 2 hours then switched to 950 mL 0.05M monobasic potassiumphosphate buffer adjusted to pH 6.8 at a temperature of 37° C. and apaddle speed of 75 rpm.

In a fourth additional embodiment, the invention provides a modifiedrelease formulation of gamma-hydroxybutyrate, preferably comprisingimmediate release and modified release portions, wherein the formulationreleases (a) at least 80% of its gamma-hydroxybutyrate at 3 hours whentested in a dissolution apparatus 2 according to USP 38 <711> in 900 mLof 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of37° C. and a paddle speed of 75 rpm, and (b) from 40% to 65%, of itsgamma-hydroxybutyrate at one hour and three hours when tested in adissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1Nhydrochloric acid at a temperature of 37° C. and a paddle speed of 75rpm.

In a fifth additional embodiment, the invention provides a modifiedrelease formulation of gamma-hydroxybutyrate, comprising immediaterelease and modified release portions, wherein (a) the formulationreleases at least 80% of its gamma-hydroxybutyrate at 3 hour 3 whentested in a dissolution apparatus 2 according to USP 38 <711> in 900 mLof 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of37° C. and a paddle speed of 75 rpm, (b) the formulation releases from40% to 65% of its gamma-hydroxybutyrate at one hour and three hours whentested in a dissolution apparatus 2 according to USP 38 <711> in 900 mLof 0.1N hydrochloric acid at a temperature of 37° C. and a paddle speedof 75 rpm, and (c) the modified release portion releases greater than80% of its gamma-hydroxybutyrate at 3 hours in a dissolution teststarted in 750 mL of 0.1N hydrochloric acid for 2 hours then switched to950 mL 0.05M monobasic potassium phosphate buffer adjusted to pH 6.8 ata temperature of 37° C. and a paddle speed of 75 rpm.

In a sixth additional embodiment, the invention provides a modifiedrelease formulation of gamma-hydroxybutyrate, comprising immediaterelease and modified release portions, wherein (a) the formulationreleases at least 80% of its gamma-hydroxybutyrate at 3 hours whentested in a dissolution apparatus 2 according to USP 38 <711> in 900 mLof 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of37° C. and a paddle speed of 75 rpm, (b) the formulation releases 40% to65%, of its gamma-hydroxybutyrate at one hour and at three hours whentested in a dissolution apparatus 2 according to USP 38 <711> in 900 mLof 0.1N hydrochloric acid at a temperature of 37° C. and a paddle speedof 75 rpm, (c) the formulation releases greater than 60% of itsgamma-hydroxybutyrate at 10 hours when tested in a dissolution apparatus2 according to USP 38 <711> in 900 mL of 0.1N hydrochloric acid at atemperature of 37° C. and a paddle speed of 75 rpm, and (d) the modifiedrelease portion releases greater than 80% of its gamma-hydroxybutyrateat 3 hours in a dissolution test started in 750 mL of 0.1N hydrochloricacid for 2 hours then switched to 950 mL 0.05M monobasic potassiumphosphate buffer adjusted to pH 6.8 at a temperature of 37° C. and apaddle speed of 75 rpm.

In a seventh additional embodiment, the invention provides a modifiedrelease formulation of gamma-hydroxybutyrate, preferably comprisingimmediate release and modified release portions, wherein the formulationreleases (a) at least 80% of its gamma-hydroxybutyrate at 1 hour whentested in a dissolution apparatus 2 according to USP 38 <711> in 900 mLof 0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of37° C. and a paddle speed of 75 rpm, and (b) from 40% to 65%, of itsgamma-hydroxybutyrate at one hour and three hours when tested in adissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1Nhydrochloric acid at a temperature of 37° C. and a paddle speed of 75rpm.

In an eighth additional embodiment, the invention provides a modifiedrelease formulation of gamma-hydroxybutyrate, comprising immediaterelease and modified release portions, wherein (a) the formulationreleases at least 80% of its gamma-hydroxybutyrate at 1 hour when testedin a dissolution apparatus 2 according to USP 38 <711> in 900 mL of0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of37° C. and a paddle speed of 75 rpm, (b) the formulation releases from40% to 65% of its gamma-hydroxybutyrate at one hour and three hours whentested in a dissolution apparatus 2 according to USP 38 <711> in 900 mLof 0.1N hydrochloric acid at a temperature of 37° C. and a paddle speedof 75 rpm, and (c) the modified release portion releases greater than80% of its gamma-hydroxybutyrate at 3 hours in a dissolution teststarted in 750 mL of 0.1N hydrochloric acid for 2 hours then switched to950 mL 0.05M monobasic potassium phosphate buffer adjusted to pH 6.8 ata temperature of 37° C. and a paddle speed of 75 rpm.

In a ninth additional embodiment, the invention provides a modifiedrelease formulation of gamma-hydroxybutyrate, comprising immediaterelease and modified release portions, wherein (a) the formulationreleases at least 80% of its gamma-hydroxybutyrate at 1 hour when testedin a dissolution apparatus 2 according to USP 38 <711> in 900 mL of0.05M monobasic potassium phosphate buffer pH 6.8 at a temperature of37° C. and a paddle speed of 75 rpm, (b) the formulation releases 40 to65%, of its gamma-hydroxybutyrate at one hour and at three hours whentested in a dissolution apparatus 2 according to USP 38 <711> in 900 mLof 0.1N hydrochloric acid at a temperature of 37° C. and a paddle speedof 75 rpm, (c) the formulation releases greater than 60% of itsgamma-hydroxybutyrate at 10 hours when tested in a dissolution apparatus2 according to USP 38 <711> in 900 mL of 0.1N hydrochloric acid at atemperature of 37° C. and a paddle speed of 75 rpm, and (d) the modifiedrelease portion releases greater than 80% of its gamma-hydroxybutyrateat 3 hours in a dissolution test started in 750 mL of 0.1N hydrochloricacid for 2 hours then switched to 950 mL 0.05M monobasic potassiumphosphate buffer adjusted to pH 6.8 at a temperature of 37° C. and apaddle speed of 75 rpm.

EXAMPLES Example 1. Formulations

Tables 1a-1d provide the qualitative and quantitative compositions ofsodium oxybate IR microparticles, MR microparticles, and mixtures of IRand MR microparticles. The physical structure of the microparticlesshowing the qualitative and quantitative composition of the IR and MRmicroparticles is depicted in FIG. 1.

Briefly, sodium oxybate immediate release (IR) microparticles wereprepared as follows: 1615.0 g of sodium oxybate and 85.0 g ofpolyvinylpyrrolidone (Povidone K30-Plasdone™ K29/32 from ISP) weresolubilized in 1894.3 g of absolute ethyl alcohol and 1262.9 g of water.The solution was entirely sprayed onto 300 g of microcrystallinecellulose spheres (Cellets™ 127) in a fluid bed spray coater apparatus.IR Microparticles with volume mean diameter of about 270 microns wereobtained.

Sodium oxybate modified release (MR) microparticles were prepared asfollows: 22.8 g of methacrylic acid copolymer Type C (Eudragit™L100-55), 45.8 g of methacrylic acid copolymer Type B (Eudragit™ S100),102.9 g of hydrogenated cottonseed oil (Lubritab™), were dissolved in1542.9 g of isopropanol at 78° C. The solution was sprayed entirely onto400.0 g of the sodium oxybate IR microparticles described above in afluid bed spray coater apparatus with an inlet temperature of 48° C.,spraying rate around 11 g per min and atomization pressure of 1.3 bar.MR microparticles were dried for two hours with inlet temperature set to56° C. MR microparticles with mean volume diameter of about 320 micronswere obtained.

The finished composition, which contains a 50:50 mixture of MR and IRmicroparticles calculated on their sodium oxybate content, was preparedas follows: 353.36 g of the above IR microparticles, 504.80 g of theabove MR microparticles, 14.27 g of malic acid (D/L malic acid), 6.34 gof xanthan gum (Xantural™ 75 from Kelco), 9.51 g of carrageenan gum(Viscarin™ PH209 from FMC Biopolymer), 9.51 g of hydroxyethylcellulose(Natrosol™ 250M from Ashland) and 4.51 g of magnesium stearate weremixed. Individual samples of 7.11 g (corresponding to a 4.5 g dose ofsodium oxybate with half of the dose as immediate-release fraction andhalf of the dose as modified release fraction) were weighed.

TABLE 1a Composition of IR Microparticles Component Function Quantityper 2.25 g dose (g) Sodium oxybate Drug substance 2.25 MicrocrystallineCore 0.418 cellulose spheres Povidone K30 Binder and excipient 0.118 indiffusion coating Ethyl alcohol Solvent Eliminated during processingPurified water Solvent Eliminated during processing Total 2.786

TABLE 1b Composition of MR Microparticles Quantity per ComponentFunction 4.5 g dose (g) IR Microparticles Core of MR 2.786microparticles Hydrogenated Vegetable Oil Coating excipient 0.716Methacrylic acid Copolymer Coating excipient 0.159 Type C Methacrylicacid Copolymer Coating excipient 0.318 Type B Isopropyl alcohol SolventEliminated during processing Total 3.981

TABLE 1c Qualitative Finished Composition Quantity per ComponentFunction 4.5 g dose (g) MR microparticles Modified release fraction3.981 of sodium oxybate IR microparticles Immediate release fraction2.786 of sodium oxybate Malic acid Acidifying agent 0.113 Xanthan gumSuspending agent 0.050 Hydroxyethylcellulose Suspending agent 0.075Carrageenan gum Suspending agent 0.075 Magnesium stearate Lubricant0.036 Total 7.116

TABLE 1d Quantitative finished composition Quantity per ComponentFunction 4.5 g dose (g) Sodium oxybate Drug substance 4.5Microcrystalline cellulose spheres Core 0.836 Povidone K30 Binder 0.237Hydrogenated Vegetable Oil Coating excipient 0.716 Methacrylic acidCopolymer Type C Coating excipient 0.159 Methacrylic acid Copolymer TypeB Coating excipient 0.318 Malic acid Acidifying agent 0.113 Xanthan gumSuspending agent 0.050 Hydroxyethylcellulose Suspending agent 0.075Carrageenan gum Suspending agent 0.075 Magnesium stearate Lubricant0.036 Total 7.116

Example 1bis: Alternative Formulation

An alternative formulation to the formulation described in example 1 isdescribed in Example 1bis.

Sodium oxybate immediate release (IR) microparticles were prepared bycoating the IR microparticles described in example 1 with a top coatlayer. Microparticles were prepared as follows: 170.0 of hydroxypropylcellulose (Klucel™ EF Pharm from Hercules) were solubilized in 4080.0 gof acetone. The solution was entirely sprayed onto 1530.0 g of the IRmicroparticles of Example 1 in a fluid bed spray coater apparatus. IRMicroparticles with volume mean diameter of about 298 microns wereobtained (see Table 1bis-a).

Sodium oxybate modified release (MR) microparticles were prepared asdescribed in example 1 (see Table 1b).

The finished composition, which contains a 50:50 mixture of MR and IRmicroparticles based on their sodium oxybate content, was prepared asfollows: 412.22 g of the above IR microparticles, 530.00 g of the aboveMR microparticles, 29.96 g of malic acid (D/L malic acid), 4.96 g ofxanthan gum (Xantural™ 75 from Kelco), 4.96 g of colloidal silicondioxide (Aerosil™ 200 from Degussa) and 9.92 g of magnesium stearatewere mixed. Individual samples of 7.45 g (corresponding to a 4.5 g doseof sodium oxybate with half of the dose in an immediate-release fractionand half of the dose in a modified release fraction) were weighed (seeTable 1bis-b and 1bis-c).

TABLE 1bis-a Composition of IR Microparticles Quantity per ComponentFunction 2.25 g dose (g) Sodium oxybate Drug substance 2.25 Microcrystalline cellulose Core 0.418 spheres Povidone K30 Binder andexcipient in 0.118 diffusion coating Hydroxypropyl cellulose Top coat0.310 Ethyl alcohol Solvent Eliminated during processing Purified waterSolvent Eliminated during processing Acetone Solvent Eliminated duringprocessing Total 3.096

TABLE 1bis-b Qualitative Finished Composition Quantity per ComponentFunction 4.5 g dose (g) MR microparticles Modified release fraction of3.981 sodium oxybate IR microparticles Immediate release fraction of3.096 sodium oxybate Malic acid Acidifying agent 0.225 Xanthan gumSuspending agent 0.037 Colloidal silicon dioxide Gliding agent 0.037Magnesium stearate Lubricant 0.075 Total 7.451

TABLE 1bis-c Quantitative finished composition Quantity per ComponentFunction 4.5 g dose (g) Sodium oxybate Drug substance 4.5Microcrystalline cellulose spheres Core 0.836 Povidone K30 Binder 0.237Hydroxypropyl cellulose Top coat 0.310 Hydrogenated Vegetable OilCoating excipient 0.716 Methacrylic acid Copolymer Type C Coatingexcipient 0.159 Methacrylic acid Copolymer Type B Coating excipient0.318 Malic acid Acidifying agent 0.225 Xanthan gum Suspending agent0.037 Colloidal silicon dioxide Gliding agent 0.037 Magnesium stearateLubricant 0.075 Total 7.451

Compared to the finished composition described in example 1, thisalternative composition has the following characteristics: same MRmicroparticles, same IR microparticles but with a top coat, increasedamount of malic acid, only one suspending agent (xanthan gum) andpresence of a glidant.

Finished compositions from Example 1 and 1bis exhibit substantially thesame in-vitro dissolution profiles (see FIGS. 7 and 8).

Example 2: In Vitro Release Profiles of IR, MR and Finished Compositionsof Formulations of Examples 1 and 1bis Dissolution Testing of IRMicroparticles

The dissolution profile of 2786 mg of IR microparticles of Example 1,corresponding to 2250 mg of sodium oxybate per vessel, was determined in0.1N HCl dissolution medium using a USP apparatus 2. Dissolution mediumtemperature was maintained at 37.0±0.5° C., and the rotating paddlespeed was set at 100 rpm. The release profile of the IR microparticlesis shown in FIG. 2 and Table 2a. All the sodium oxybate was released at1 hour.

TABLE 2a Percent Sodium Oxybate Released in 0.1N HCl for IRmicroparticles of sodium oxybate prepared according to Example 1 Time(min) % released 0 0 5 94 10 97 15 97 30 98 60 98Dissolution Testing of IR Microparticles from Example 1bis

The dissolution profile of 3096 mg of IR microparticles of Example 1bis,corresponding to 2250 mg of sodium oxybate per vessel, was determined in0.1N HCl dissolution medium using a USP apparatus 2. Dissolution mediumtemperature was maintained at 37.0±0.5° C., and the rotating paddlespeed was set at 100 rpm. The release profile of the IR microparticlesis shown in FIG. 2 and Table 2b. All the sodium oxybate was released at1 hour.

TABLE 2b Percent Sodium Oxybate Released in 0.1N HCl for IRmicroparticles of sodium oxybate prepared according Example 1bis Time(min) % Released 0 0 5 91 10 99 15 100 30 101 60 100Dissolution Testing of MR Microparticles from Example 1—Protocol (2 h0.1N HCl/Phosphate Buffer pH 6.8)

49.1 g of MR microparticles from Example 1 were mixed with 0.5 g ofmagnesium stearate (from Peter Graven) and 0.25 g of colloidal silicondioxide (Aerosil™ 200 from Evonik). The dissolution profile of 4040 mgof the mixture which corresponds to 2250 mg of sodium oxybate per vesselwas determined using the USP apparatus 2. Dissolution medium temperaturewas maintained at 37.0±0.5° C., and the rotating paddle speed was set at75 rpm.

After 2 hours in 750 mL of 0.1N HCl medium, 6.5 g of monobasic potassiumphosphate was added to the dissolution vessel. pH and volume were thenrespectively adjusted to 6.8 and 950 mL, as needed by the addition ofNaOH and water. The potassium phosphate concentration was equal to 0.05M in the dissolution medium after pH and volume adjustment.

The release profile of the MR microparticles is shown in FIG. 3 andTable 2c. The sodium oxybate was not released in the 0.1N HCldissolution medium during two hours. After the switch to pH 6.8dissolution medium, all the sodium oxybate was released within 30minutes.

TABLE 2c Percent Sodium Oxybate Released in two sequential dissolutionmedia (0.1HCl for 2 hours, then phosphate buffer pH 6.8) for MRmicroparticles of sodium oxybate prepared according to Example 1 Time(h) % released 0 0 1 1 2 2 2.25 33 2.5 97 3 103 4 104 6 103

FIG. 4 overlays the dissolution profile of the MR microparticles ofExample 1 with the dissolution profile for MR microparticles reported inSupernus U.S. Pat. No. 8,193,211, FIG. 3. It shows that the dissolutionprofiles are different and that the MR microparticles according to thepresent invention release greater than 80% of their sodium oxybate at 3hours, whereas the MR microparticles described in Supernus U.S. Pat. No.8,193,211, FIG. 3 do not and exhibit a much slower release profile.

Dissolution Testing of Finished Composition According to Example 1 inDeionized Water

The dissolution profile of the quantity equivalent to 4.5 g sodiumoxybate of the finished composition according Example 1 was determinedin 900 mL of deionized water using the USP apparatus 2. The dissolutionmedium was maintained at 37.0±0.5° C. and the rotating paddle speed wasfixed at 50 rpm. The release profile is shown in FIG. 5 and Table 2d.The IR fraction of sodium oxybate was solubilized in 15 minutes. Therelease of sodium oxybate from the modified-release fraction startedafter approximately 4 hours with 90% of the total dose released at 6hours.

TABLE 2d Percent Sodium Oxybate Released in deionized water for finishedcomposition of sodium oxybate prepared according to Example 1 Time (h) %released 0 0 0.25 53 1 52 2 54 3 55 4 58 5 69 6 92 7 96 8 97

An overlay of the release profile of the finished formulation of Example1 versus that reported in USP 2012/0076865 FIG. 2 is shown in FIG. 6. Itshows that the dissolution profiles are different. The formulationdescribed in USP 2012/0076865 FIG. 2 does not exhibit a lag phase afterthe dissolution of the immediate release part.

Release Testing of Different Batches of MR Microparticles and FinishedDosage Forms

In vitro release profiles obtained in 900 mL of 0.1N HCl dissolutionmedium for different batches of modified release (MR) microparticlesprepared according to Example 1 are described below in Table 2e. Thedissolution profile of 4040 mg of microparticles corresponding to 2250mg of sodium oxybate per vessel is determined using the USP apparatus 2.Dissolution medium temperature was maintained at 37.0±0.5° C., and therotating paddle speed was set at 100 rpm.

TABLE 2e Percent Sodium Oxybate Released in 0.1N HCl Dissolution Mediumfrom different manufacturing lots of MR Particles of Example 1 Time Lot1 Lot 2 Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 0.25 2.22 0.62 0.42 0.860.56 1.03 0.69 0.26 1.0 2.59 1.14 1.23 1.48 0.96 2.15 1.43 0.97 2.003.07 1.71 2.09 1.94 1.36 3.16 2.17 1.39 3 3.55 2.31 2.75 2.29 1.76 4.082.82 1.80 4.0 4.23 3.03 3.53 2.75 2.18 4.92 3.50 2.31 6 7.99 7.68 8.695.33 3.78 7.52 5.70 8.10 8.0 37.44 33.84 33.84 26.20 17.00 21.59 21.0237.27 10 77.09 69.85 65.51 61.77 49.89 50.98 53.48 67.64 12 91.26 85.7284.25 83.55 77.65 75.68 78.00 82.66 16 96.15 90.48 95.35 97.34 96.9495.19 96.17 90.35

In vitro release profiles obtained in 0.1N HCl for three batches offinished composition comprising IR (50% w/w sodium oxybate dose) and MRmicroparticles (50% w/w sodium oxybate dose), prepared as described inExample 1, are provided in Table 2f. The sodium oxybate dose per vesselwas 4.5 g, 6 g and 7.5 g respectively and dissolution was determined in900 mL of 0.1N HCl dissolution medium using the USP apparatus 2. Thedissolution medium was maintained at 37.0±0.5° C. and the rotatingpaddle speed was fixed at 100 rpm. Single dose units were poured in acontainer containing 50 mL of tap water. After 5 minutes, the suspensionwas poured in the dissolution vessel containing 840 mL of 0.1N HCldissolution medium. 10 mL of water were used to rinse the container andwere added to the dissolution vessel.

TABLE 2f Percent Sodium Oxybate Released in 0.1N HCl Dissolution Mediumfor three batches of finished composition prepared according to Example1 Time (hour) Batch 1 Batch 2 Batch 3 0.5 50 49 50 1 50 50 50 3 50 50 506 52 52 53 8 61 64 63 12 90 93 97 16 96 94 95

FIG. 7 and Table 2g depict dissolution profiles determined using a USPapparatus 2 in a 900 mL in 0.1N HCl dissolution medium of four finishedcompositions, two prepared according to Example 1 and two preparedaccording to Example 1bis. The dissolution medium was maintained at37.0±0.5° C. and the rotating paddle speed was fixed at 100 rpm. Itshows that the composition according to the invention releases from 10to 65% of its sodium oxybate at 1 and 3 hours and releases greater than60% at 10 hours.

TABLE 2g Percent Sodium Oxybate Released in 0.1N HCl Dissolution Mediumfor four batches of finished compositions, two prepared according toExample 1 and two prepared according to Example 1bis Time (hour) Example1bis Example 1bis Example 1 Example 1 0  0  0  0  0 0.25 Nd Nd 52 50 0.551 50 Nd Nd 1 51 50 54 51 3 51 50 54 52 6 55 52 55 53 8 72 61 60 57 10Nd Nd 73 70 12 86 90 85 83 16 88 96 96 94 20 Nd Nd 99 98 Nd: notdetermined

FIG. 8 and Table 2h depict dissolution profiles determined using a USPapparatus 2 in a 900 mL phosphate buffer pH 6.8 dissolution medium forfour finished compositions prepared according to Example 1 or 1bis. Thedissolution medium was maintained at 37.0±0.5° C. and the rotatingpaddle speed was fixed at 100 rpm. It shows that the compositionaccording to the invention releases more than 80% of its sodium oxybateat 3 hours.

TABLE 2h Percent Sodium Oxybate Released in phosphate buffer pH 6.8Dissolution Medium for four batches of finished compositions, twoprepared according to Example 1 and two prepared according to Example1bis Time (hour) Example 1bis Example 1bis Example 1 Example 1 0  0  0 0  0 0.25 Nd Nd  75  84 0.5  99  98 Nd Nd 1 101 101 100 102 1.5 101 101106 108 2 100 100 Nd Nd 3 103 100 Nd Nd 4 103 100 Nd Nd 6 102  99 101102 8 103  99 101 105 10 103  99 101 Nd 12 101  99 101 102 16 Nd Nd 100101 20 Nd Nd  99  98 Nd: not determined

Release Testing of MR Microparticles and Finished Compositions—Effect ofPaddle Speed:

FIG. 9 and Table 2i depict dissolution profiles in 0.1N HCl of a batchof MR microparticles prepared according to Example 1. The dissolutionprofile of 4040 mg of microparticles corresponding to 2250 mg of sodiumoxybate per vessel was determined using the USP apparatus 2. Thedissolution medium temperature was maintained at 37.0±0.5° C., and therotating paddle speed was set at 75 or 100 rpm.

TABLE 2i Percent Sodium Oxybate Released in 0.1N HCl Dissolution Mediumfor MR microparticles prepared according to Example 1 Time (hour) 75 rpm100 rpm 0 0 0 0.25 1 1 1 2 1 2 2 2 3 3 2 4 3 3 6 6 5 8 28 26 10 65 62 1286 84 16 97 97

FIG. 10 and Table 2j depict dissolution profiles in 0.1N HCl of afinished composition prepared according to Example 1. The dose pervessel was 4.5 g and dissolution was determined in 900 mL of dissolutionmedium using the USP apparatus 2. The dissolution medium temperature wasmaintained at 37.0±0.5° C. and the rotating paddle speed was set at 75or 100 rpm.

Single dose units were poured in a container containing 50 mL of tapwater. After 5 minutes, the suspension was poured in the dissolutionvessel containing 840 mL of 0.1N HCl medium. 10 mL of water were used torinse the container and were added to the dissolution vessel.

TABLE 2j Percent Sodium Oxybate Released in 0.1N HCl Dissolution Mediumfor finished composition prepared according to Example 1 Time (hour) 75rpm 100 rpm 0 0 0 0.25 48 47 1 53 52 3 54 53 6 56 56 8 65 65 10 82 79 1292 89 16 97 96 20 98 98

Example 3. In Vivo Pharmacokinetic Study of Finished CompositionAccording to Example 1bis

Pharmacokinetic testing was undertaken in vivo in healthy humanvolunteers according to the principles described in FDA's March 2003Guidance for Industry on BIOAVAILABILITY AND BIOEQUIVALENCE STUDIES FORORALLY ADMINISTERED DRUG PRODUCTS—GENERAL CONSIDERATIONS. All testingwas performed in subjects two hours after eating a standardized dinner.Xyrem® doses were administered in two equipotent doses four hours apart.All other tested doses were manufactured as described in Example 1bis.The standardized dinner consisted of 25.5% fat, 19.6% protein, and 54.9%carbohydrates.

The finished composition of Example 1bis given as a 4.5 g once-nightlydose rather than a standard Xyrem® dosing twice (2×2.25 g) nightly 4hours apart, produced a dramatically different pharmacokinetic profilethan Xyrem® as shown in FIG. 11. As summarized below (Tables 3a and 3b),4.5 g nighttime doses of finished composition of the inventionequivalent to twice-nightly doses of Xyrem® (2×2.25 g) provided somewhatless total exposure to sodium oxybate with a later median T_(max) thanthe initial Xyrem® dose. The relative bioavailability was about 88%.Composition according to the invention avoids the high second-dose peakconcentration of Xyrem® and therefore does not exhibit the substantialbetween-dose fluctuations in concentration, while achieving a comparablemean C_(8h).

TABLE 3a Pharmacokinetic Parameters of finished composition of Example1bis vs. Xyrem ® Mean Cmax (μg/mL) Mean AUCinf Median Tmax (% CV) (h *μg/mL) (hour) (min-max) Finished composition of 44.35 (38) 188.88 (44)1.5 (0.5-4) Example 1bis 4.5 g Xyrem ® 2 × 2.25 g 1st dose: 33.41 (41)214.32 (48) 1st dose: 1.00 (0.5-2) 2nd dose: 65.91 (40) 2nd dose: 4.50(4.33-6.5)

TABLE 3b Mean plasma concentration of gamma-hydroxybutyrate(microgram/mL) versus time of finished composition of Example 1bis andXyrem ® Finished composition Finished composition Example 1bis 4.5 gExample 1bis 6.0 g Finished composition (2 h after meal) pooled (2 hafter meal) pooled Example 1bis 7.5 g Xyrem ® (2 × 2.25 g) Time (hour)mean (N = 26) mean (N = 19) (2 h after meal) (N = 11) part I (N = 15) 00.00 0.00 0.00 0.00 0.5 29.31 36.44 43.19 27.44 1 34.93 49.97 63.3228.97 1.5 36.63 54.66 73.40 26.12 2 36.78 54.82 67.96 21.11 2.5 33.3553.05 66.59 NA 3 30.28 50.25 62.13 13.93 3.5 27.30 47.22 59.45 10.25 423.66 43.06 57.40 6.92 4.5 19.89 39.13 50.85 57.33 5 16.55 34.28 45.0952.27 5.5 13.62 32.11 44.94 43.55 6 12.40 25.84 42.36 35.20 6.5 11.2522.36 41.02 27.44 7 11.27 18.07 40.76 19.36 7.5 9.65 15.41 35.83 13.88 86.86 12.80 30.94 9.24 10 1.08 2.38 7.99 2.64 12 NC 0.52 1.47 NC NC: NotCalculated

The pharmacokinetic profile of a single 6 g dose of finished compositionproduced according to Example 1bis was also tested and found to have asimilar pharmacokinetic profile as the 4.5 g dose. FIG. 12 provides apharmacokinetic profile comparison of a single 4.5 g or 6 g dose offinished composition according to Example 1bis in the same 7 subjects.The pharmacokinetic profile for a 7.5 g dose of finished formulationproduced according to Example 1bis was also obtained. FIG. 13 and Table3c provide data on a single 4.5 g, 6 g and 7.5 g dose, showing effectson T_(max), C_(max), C_(8h), AUC_(8h) and AUC_(inf) related to dosestrength. The 7.5 g dose achieved a mean C_(8h) equal to about 31microgram/mL which represents approximately 128.5% of the C_(8h)obtained for Xyrem® dosed 2×3.75 g which was extrapolated to beapproximately 24.07 microgram/mL from published data. The 7.5 g doseachieved a ratio of AUC_(8h) to AUC_(inf) of about 0.89, whereas theratio was 0.83 and 0.93 for the 4.5 g and 6 g doses respectively.

TABLE 3c Pharmacokinetic Parameters of 4.5 g, 6 g, and 7.5 g of finishedcomposition produced according to Example 1bis Finished composition MeanC_(max) Mean AUC_(inf) Mean AUC_(8 h) Mean C_(8 h) according to (μg/mL)(% (h * μg/mL) (h * μg/mL) (% Median T_(max) (μg/mL) (% Example 1bis CV)(% CV) CV) (h) (min-max) CV) 4.5 g 44.35 (38) 188.88 (47) 174.68 (48)1.5 (0.5-4)   6.86 (84)   6 g 65.46 (35) 307.34 (48) 290.97 (47) 3(0.5-5.5) 12.8 (82) 7.5 g 88.21 (30) 454.99 (34) 404.88 (31) 2 (0.5-6)  30.94 (34) 

FIG. 14 and table 3d compare the pharmacokinetic parameters AUC_(inf)and C_(8h) obtained for 7.5 g of a finished composition according toExample 1bis to the same parameters calculated for 2×4.5 g, i.e. 9 gtotal dose of Xyrem®. The data show that a 7.5 g dose of a formulationaccording to the invention given once nightly exhibits a similar PKprofile to 9 g of Xyrem® given in two separate equal doses.

TABLE 3d Pharmacokinetic Parameters of 7.5 g of finished compositionproduced according to Example 1bis compared to 2 × 4.5 g of Xyrem ®Ratio (%) Ratio (%) AUC_(inf) C_(8 h) Mean Mean composition compositionC_(8 h) AUC_(inf) to AUC_(inf) to C_(8 h) (μg/mL) (μg/mL * h) Xyrem ®Xyrem ® Xyrem ® 2 × 4.5 g 28.9 518 NA NA Finished 30.9 455 88% 107%composition according to Example 1bis 7.5 g

Example 4. Alternative Formulation

Tables 4a-4d provide the qualitative and quantitative compositions of IRmicroparticles, MR microparticles, and mixtures of IR and MRmicroparticles. The physical structure of the microparticles showing thequalitative and quantitative composition of the IR and MR microparticlesis depicted in FIG. 15.

Briefly, sodium oxybate immediate release (IR) microparticle wereprepared as follows: 1615.0 g of Sodium Oxybate and 85.0 g ofpolyvinylpyrrolidone (Povidone K30-Plasdone™ K29/32 from ISP) weresolubilized in 1894.3 g of absolute ethyl alcohol and 1262.9 g of water.The solution was entirely sprayed onto 300 g of microcrystallinecellulose spheres (Cellets™ 127) in a fluid bed spray coater apparatus.IR microparticles with volume mean diameter of about 270 microns wereobtained.

Sodium oxybate modified release (MR) microparticles were prepared asfollows: 4.0 g of Methacrylic acid copolymer Type C (Eudragit™ L100-55),49.3 g of Methacrylic acid copolymer Type B (Eudragit™ S100), 80 g ofHydrogenated cottonseed oil (Lubritab™), were dissolved in 1200.0 g ofisopropanol at 78° C. The solution was sprayed entirely on 400.0 g of IRmicroparticles prepared above in a fluid bed spray coater apparatus withan inlet temperature 48° C., spraying rate around 11 g per min andatomization pressure 1.3 bar. MR microparticles were dried for two hourswith inlet temperature set to 56° C. MR microparticles with volume meandiameter of about 330 microns were obtained.

The finished composition, which contained a 50:50 mixture of MR and IRmicroparticles calculated on their sodium oxybate content, was preparedas follows: 27.86 g of IR microparticles, 37.15 g of MR microparticles,1.13 g of malic acid (D/L malic acid), 0.50 g of xanthan gum (Xantural™75 from Kelco), 0.75 g of carrageenan gum (Viscarin™ PH209 from FMCBiopolymer), 0.75 g of hydroxyethylcellulose (Natrosol™ 250M fromAshland) and 0.34 g of magnesium stearate were mixed. Individual samplesof 6.85 g (corresponding to a 4.5 g sodium oxybate dose with half of thedose as immediate-release fraction and half of the dose as modifiedrelease fraction) were weighed.

TABLE 4a Composition of IR Microparticles Quantity per ComponentFunction 2.25 g dose (g) Sodium oxybate Drug substance 2.25Microcrystalline cellulose Core 0.418 spheres Povidone K30 Binder andexcipient in 0.118 diffusion coating Ethyl alcohol Solvent Eliminatedduring processing Purified water Solvent Eliminated during processingTotal 2.786

TABLE 4b Composition of MR Microparticles Quantity per ComponentFunction 2.25 g dose (g) IR Microparticles Core of MR 2.786Microparticles Hydrogenated Vegetable Oil Coating excipient 0.557Methacrylic acid Copolymer Coating excipient 0.028 Type C Methacrylicacid Copolymer Coating excipient 0.344 Type B Isopropyl alcohol SolventEliminated during processing Total 3.715

TABLE 4c Qualitative Finished Composition Quantity per ComponentFunction 4.5 g dose (g) MR microparticles Modified release fraction3.715 of sodium oxybate IR microparticles Immediate release fraction2.786 of sodium oxybate Malic acid Acidifying agent 0.113 Xanthan gumSuspending agent 0.050 Hydroxyethylcellulose Suspending agent 0.075Carrageenan gum Suspending agent 0.075 Magnesium stearate Lubricant0.034 Total 6.848

TABLE 4d Quantitative finished composition Quantity per ComponentFunction 4.5 g dose (g) Sodium oxybate Drug substance 4.5Microcrystalline cellulose Core 0.836 spheres Povidone K30 Binder 0.237Hydrogenated Vegetable Oil Coating excipient 0.557 Methacrylic acidCopolymer Coating excipient 0.028 Type C Methacrylic acid CopolymerCoating excipient 0.344 Type B Malic acid Acidifying agent 0.113 Xanthangum Suspending agent 0.050 Hydroxyethylcellulose Suspending agent 0.075Carrageenan gum Suspending agent 0.075 Magnesium stearate Lubricant0.034 Total 6.848

Example 4bis

An alternative formulation to example 4 is described in example 4bis.Sodium oxybate immediate release (IR) microparticles were prepared bycoating the IR microparticles described in example 4 with a top coatlayer. IR Microparticles were prepared as follows: 170.0 ofhydroxypropyl cellulose (Klucel™ EF Pharm from Hercules) weresolubilized in 4080.0 g of acetone. The solution was entirely sprayedonto 1530.0 g of the IR microparticles of Example 4 in a fluid bed spraycoater apparatus. IR Microparticles with volume mean diameter of about298 microns were obtained (see Table 4bis-a).

Sodium oxybate modified release (MR) microparticles were prepared asdescribed in example 4 (see Table 4b).

The finished composition, which contains a 50:50 mixture of MR and IRmicroparticles calculated based on sodium oxybate content, was preparedas follows: 424.99 g of the above IR microparticles, 509.98 g of theabove MR microparticles, 30.89 g of malic acid (D/L malic acid), 4.93 gof xanthan gum (Xantural™ 75 from Kelco), 4.93 g of colloidal silicondioxide (Aerosil™ 200 from Degussa) and 9.86 g of magnesium stearatewere mixed. Individual samples of 7.18 g (corresponding to a 4.5 g doseof sodium oxybate with half of the dose as an immediate-release fractionand half of the dose as a modified release fraction) were weighed. (seeTables 4bis-b and 4bis-c).

TABLE 4bis-a Composition of IR Microparticles Quantity per ComponentFunction 2.25 g dose (g) Sodium oxybate Drug substance 2.25Microcrystalline cellulose Core 0.418 spheres Povidone K30 Binder andexcipient in 0.118 diffusion coating Hydroxypropyl cellulose Top coat0.310 Ethyl alcohol Solvent Eliminated during processing Purified waterSolvent Eliminated during processing Acetone Solvent Eliminated duringprocessing Total 3.096

TABLE 4bis-b Qualitative Finished Composition Quantity per ComponentFunction 4.5 g dose (g) MR microparticles Modified release fraction of3.715 sodium oxybate IR microparticles Immediate release fraction of3.096 sodium oxybate Malic acid Acidifying agent 0.225 Xanthan gumSuspending agent 0.036 Colloidal silicon dioxide Gliding agent 0.036Magnesium stearate Lubricant 0.072 Total 7.180

TABLE 4bis-c Quantitative finished composition Quantity per ComponentFunction 4.5 g dose (g) Sodium oxybate Drug substance 4.5Microcrystalline cellulose spheres Core 0.836 Povidone K30 Binder 0.237Hydroxypropyl cellulose Top coat 0.310 Hydrogenated Vegetable OilCoating excipient 0.557 Methacrylic acid Copolymer Type C Coatingexcipient 0.028 Methacrylic acid Copolymer Type B Coating excipient0.344 Malic acid Acidifying agent 0.225 Xanthan gum Suspending agent0.036 Colloidal silicon dioxide Gliding agent 0.036 Magnesium stearateLubricant 0.072 Total 7.180

Compared to the finished composition described in example 4, thisalternative composition has the following characteristics: same MRmicroparticles, same IR microparticles but with a top coat, increasedamount of malic acid, only one suspending agent (xanthan gum) andpresence of a glidant.

Example 5 In Vitro Release Profiles of IR, MR and Finished Compositionsof Formulation of Example 4 and 4bis

Dissolution Testing of MR Microparticles from Example 4—Protocol (2 h0.1N HCl/Phosphate Buffer pH 6.8)

49.1 g of MR microparticles from Example 4 were mixed with 0.5 g ofmagnesium stearate (from Peter Greven) and 0.25 g of colloidal silicondioxide (Aerosil™ 200 from Evonik).

The dissolution profile of 3770 mg of the mixture which correspond to2250 mg of sodium oxybate per vessel was determined using the USPapparatus 2. Dissolution medium temperature was maintained at 37.0±0.5°C., and the rotating paddle speed was set at 75 rpm.

After 2 hours in 750 mL of 0.1N HCl dissolution medium, 6.5 g ofmonobasic potassium phosphate was added in the dissolution vessel. pHand volume were then respectively adjusted to 6.8 and 950 mL. Thepotassium phosphate concentration was equal to 0.05 M in the dissolutionmedium after pH and volume adjustment. The release profile is shown inFIG. 16 and Table 5a.

TABLE 5a Percent Sodium Oxybate Released in two sequential dissolutionmedia (0.1N HCl for two hours, then phosphate buffer pH 6.8) for MRmicroparticles of sodium oxybate prepared according to Example 4 %sodium Time (h) oxybate dissolved 0 0 1 1 2 2 2.25 9 2.5 40 3 89 4 102 6103

The sodium oxybate was not released in the 0.1N HCl medium during twohours. After the switch at pH 6.8, 40% of the API was released after 30minutes and 90% of API after 1 hour. FIG. 17 overlays the dissolutionprofile of the MR microparticles of Example 4 with the dissolutionprofile for MR microparticles reported in Supernus U.S. Pat. No.8,193,211, FIG. 3. It shows that the dissolution profiles are differentand especially that the MR microparticles according to the inventionrelease greater than 80% of its sodium oxybate at 3 hours, whereas theMR microparticles described in Supernus U.S. Pat. No. 8,193,211, FIG. 3do not and exhibit a much slower releasing profile.

Dissolution Testing of Finished Composition According to Example 4 inDeionized Water:

The dissolution profile of the quantity equivalent to 4.5 g of sodiumoxybate of the finished composition of the Example 4 was determined in900 mL of deionized water using the USP apparatus 2. The dissolutionmedium was maintained at 37.0±0.5° C. and the rotating paddle speed wasset at 50 rpm. The release profile of is shown in FIG. 18 and Table 5b.

TABLE 5b Percent Sodium Oxybate Released in deionized water for finishedcomposition of sodium oxybate prepared according to Example 4 Time(hour) Example 4 0 0 0.25 52 1 55 2 53 3 54 4 52 5 54 6 60 7 78 8 90

The IR fraction of sodium oxybate was solubilized in 15 minutes. Therelease of sodium oxybate from the modified release fraction startedafter 5 hours with 90% of the total dose released at 8 hours.

An overlay of the release profile of the finished composition of theExample 4 versus that reported in USP 2012/0076865 FIG. 2 is shown inFIG. 19. It shows that the dissolution profiles are different. Theformulation described in USP 2012/0076865 FIG. 2 does not exhibit a lagphase after the dissolution of the immediate release part.

FIG. 20 and Table 5c depict dissolution profiles determined using a USPapparatus 2 in a 900 mL in 0.1N HCl dissolution medium of three finishedcompositions prepared according to Example 4bis. The dissolution mediumwas maintained at 37.0±0.5° C. and the rotating paddle speed was fixedat 100 rpm. It shows that the composition according to the inventionreleases from 10 to 65% of its sodium oxybate at 1 and 3 hours andreleases greater than 60% at 10 hours.

TABLE 5c Percent Sodium Oxybate Released in 0.1N HCl Dissolution Mediumfor three batches of finished composition prepared according to Example4bis Time (Hour) Batch 1 Batch 2 Batch 3 0 0  0  0 0.25 50 Nd Nd 0.5 5150 49 0.75 51 Nd Nd 1 51 51 51 1.5 51 Nd Nd 2 51 Nd Nd 3 51 52 53 4 51Nd Nd 6 55 57 57 8 74 70 71 10 89 Nd Nd 12 93 90 92 16 94 95 97 Nd = notdetermined

FIG. 21 and Table 5d depict dissolution profile determined using a USPapparatus 2 in a 900 mL phosphate buffer pH 6.8 dissolution medium for afinished composition prepared according to Example 4bis. The dissolutionmedium was maintained at 37.0±0.5° C. and the rotating paddle speed wasset at 100 rpm. It shows that the composition according to the inventionreleases more than 80% of its sodium oxybate at 3 hours.

TABLE 5d Percent Sodium Oxybate Released in phosphate buffer pH 6.8Dissolution Medium for finished composition prepared according toExample 4bis Time (Hour) Example 4bis 0 0 0.25 54 0.5 54 0.75 55 1.0 561.5 63 2 77 3 103 4 105 6 105 8 102 10 101 12 104 16 100

Example 6. In Vivo Pharmacokinetic Study of Finished CompositionAccording to Example 4bis

Pharmacokinetic testing was undertaken in vivo in healthy humanvolunteers according to the principles described in FDA's March 2003Guidance for Industry on BIOAVAILABILITY AND BIOEQUIVALENCE STUDIES FORORALLY ADMINISTERED DRUG PRODUCTS—GENERAL CONSIDERATIONS. All testingwas performed in subjects two hours after eating a standardized dinner.Xyrem® doses were administered in two equipotent doses four hours apart.All other tested doses were manufactured as described in Example 4bis.The standardized dinner consisted of 25.5% fat, 19.6% protein, and 54.9%carbohydrates.

The finished composition of Example 4bis given as a 4.5 g once-nightlydose rather than a standard Xyrem® dosing twice (2×2.25 g) nightly 4hours apart, produced a dramatically different pharmacokinetic profilethan Xyrem® as shown in FIG. 22. As summarized below (Tables 6a and 6b),4.5 g nighttime doses of finished composition of the inventionequivalent to twice-nightly doses of Xyrem® (2×2.25 g) provided somewhatless total exposure to sodium oxybate with a later median T_(max) thanthe initial Xyrem® dose. The relative bioavailability was about 88%.Composition according to the invention avoids the high second-dose peakconcentration of Xyrem® and therefore does not exhibit the substantialbetween-dose fluctuations in concentration, while achieving a comparablemean C_(8h).

TABLE 6a Pharmacokinetic Parameters of finished composition of Example4bis vs. Xyrem ® Mean C_(max) Mean AUC_(inf) Mean AUC_(8 h) MedianT_(max) (μg/mL) (% (h * μg/mL) (h * μg/mL) (% (hour) Mean C_(8 h) CV) (%CV) CV) (min-max) (μg/mL) (% CV) Finished 43.47 (49) 188.96 (57) 179.69(57) 2 (0.5-7) 6.85 (118) composition of Example 4bis 4.5 g Xyrem ® 2 ×1^(st) dose: 214.32 (48) 202.78 (46) 1^(st) dose: 1.0 9.24 (127) 2.25 g33.41 (41) (0.5-2) 2^(nd) dose: 65.91 2^(nd) dose: 4.5 (40) (4.33-6.5)

TABLE 6b Mean plasma concentration of gamma-hydroxybutyrate(microgram/mL) versus time of finished composition of Example 4bis andXyrem ® Finished composition Example 4bis 4.5 g Xyrem ® Time (hour) (2 hafter meal) (N = 15) (2 × 2.25 g) (N = 15) 0 0.00 0.00 0.5 23.80 27.44 133.26 28.97 1.5 35.60 26.12 2 35.57 21.11 2.5 33.81 13.93 3 30.96 10.253.5 28.73 6.92 4 26.06 42.32 4.5 23.27 57.33 5 18.68 52.27 5.5 16.6743.55 6 15.55 35.20 6.5 13.07 27.44 7 11.75 19.36 7.5 9.20 13.88 8 6.859.24 10 1.94 2.64 12 NC NC NC: Not Calculated

The 4.5 g dose achieved a mean C_(8h) equal to about 6.85 microgram/mLwhich represents approximately 74.1% of the C_(8h) obtained for Xyrem®dosed 2×2.25 g. The ratio of AUC_(8h) to AUC_(inf) was about 0.89.

Example 7. In Vitro and In Vivo Pharmacokinetic Study of a ComparativeFormulation

A formulation having an in vitro dissolution profile comparable to theformulation reported in FIG. 3 of U.S. Pat. No. 8,193,211 was preparedto confirm the in vitro/in vivo correlations reported herein. Tables7a-7c provide the qualitative and quantitative compositions of the MRmicroparticles, and mixtures of IR and MR microparticles. The physicalstructure of the microparticles showing the qualitative and quantitativecomposition of the IR and MR microparticles is depicted in FIG. 23.

Briefly, sodium oxybate immediate release (IR) microparticles wereprepared according to Example 1bis. Sodium oxybate modified release (MR)microparticles were prepared in two steps:

Step 1: 106.7 g of water insoluble polymer Ethylcellulose (Ethocel™ 20Premium), 10.7 g of polyvinylpyrrolidone (Plasdone™ K30 from ISP), 10.7g of castor oil (from Olvea) and 5.3 g of Polyoxyl 40 HydrogenatedCastor Oil (Kolliphor RH40 from BASF), were dissolved in a mixture of828.0 g of acetone, 552.0 g of isopropanol and 153.3 g of water. Thesolution was sprayed entirely on 400.0 g of immediate releasemicroparticles of sodium oxybate prepared above in a fluid bed spraycoater apparatus Glatt G.P.C.G.1.1 with inlet temperature 57° C.,spraying rate around 14.5 g per min and atomization pressure 2.5 bar.Microparticles with volume mean diameter of about 310 microns wereobtained.

Step 2: 15.0 g of Methacrylic acid copolymer Type C (Eudragit™ L100-55from Evonik), 30.0 g of Methacrylic acid copolymer Type B (Eudragit™S100 from Evonik), 67.5 g of Hydrogenated cottonseed oil (Lubritab™),were dissolved in 1012.5 g of isopropanol at 78° C. The solution wassprayed entirely on 450.0 g of the above prepared microparticles in afluid bed spray coater apparatus with an inlet temperature 47° C.,spraying rate around 10.5 g per min and atomization pressure 1.3 bar. MRmicroparticles were dried for two hours with inlet temperature set to56° C. MR Microparticles with volume mean diameter of 335 microns wereobtained.

The finished composition, which contains a 60:40 mixture of MR and IRmicroparticles calculated based on their sodium oxybate content, wasprepared as follows: 326.69 g of the above IR microparticles, 735.04 gof the above MR microparticles, 23.74 g of malic acid (D/L malic acid),5.54 g of xanthan gum (Xantural™ 75 from Kelco), 5.54 g of colloidalsilicon dioxide (Aerosil™ 200 from Degussa) and 11.08 g of magnesiumstearate were mixed. Individual samples of 8.40 g (corresponding to a4.5 g dose of sodium oxybate with 40% of the dose as immediate-releasefraction and 60% of the dose as modified release fraction) were weighed.

TABLE 7a Composition of MR Microparticles Quantity per ComponentFunction 2.25 g dose (g) IR Microparticles Core of MR 2.786Microparticles Ethylcellulose 20 Coating excipient 0.743 Povidone K30Coating excipient 0.074 Polyoxyl 40 Hydrogenated Coating excipient 0.037Castor Oil Castor oil Coating excipient 0.074 Hydrogenated Vegetable OilCoating excipient 0.557 Methacrylic acid Copolymer Coating excipient0.124 Type C Methacrylic acid Copolymer Coating excipient 0.248 Type BEthyl alcohol Solvent Eliminated during processing Acetone SolventEliminated during processing Water Solvent Eliminated during processingIsopropyl alcohol Solvent Eliminated during processing Total 4.644

TABLE 7b Qualitative Composition of Finished Composition Quantity perComponent Function 4.5 g dose (g) MR microparticles Modified releasefraction 5.573 of sodium oxybate IR microparticles Immediate releasefraction 2.477 of sodium oxybate Malic acid Acidifying agent 0.180Xanthan gum Suspending agent 0.042 Colloidal silicon dioxide Glidingagent 0.042 Magnesium stearate Lubricant 0.084 Total 8.398

TABLE 7c Quantitative Composition of Finished Composition Quantity perComponent Function 4.5 g dose (g) Sodium oxybate Drug substance 4.5Microcrystalline cellulose Core 0.836 spheres Povidone K30 der andcoating excipient 0.326 Hydroxypropyl cellulose Top coat 0.248Ethylcellulose 20 Coating excipient 0.892 Polyoxyl 40 HydrogenatedCoating excipient 0.045 Castor Oil Castor oil Coating excipient 0.089Hydrogenated Vegetable Oil Coating excipient 0.669 Methacrylic acidCopolymer Coating excipient 0.149 Type C Methacrylic acid CopolymerCoating excipient 0.297 Type B Malic acid Acidifying agent 0.180 Xanthangum Suspending agent 0.042 Colloidal silicon dioxide Gliding agent 0.042Magnesium stearate Lubricant 0.084 Total 8.398

The dissolution profile obtained for the MR microparticles in twosequential dissolution media (0.1N HCl for 2 hours then phosphate bufferpH 6.8) is shown in FIG. 24 and Table 7d. These data show that thedissolution profile of the MR microparticles produced according thecomparative Example 7 was quite similar to the dissolution profile ofFIG. 3 from U.S. Pat. No. 8,193,211. In particular, the MRmicroparticles according to the comparative Example 7 do not releasemore than 80% of its sodium oxybate at 3 hours.

TABLE 7d Dissolution profile obtained for the MR microparticles ofExample 7 in two sequential dissolution media (0.1N HCl for 2 hours thenphosphate buffer pH 6.8) Time (hour) Example 7 0 0 1 0 2 1 2.25 5 2.5 443 74 64 89 6 96

The finished composition of Comparative Example 7 was tested in the samepharmacokinetic study than the finished composition of Example 1 and 4.As summarized below (Tables 7e), 4.5 g nighttime dose of finishedcomposition of the comparative Example 7 compared to twice-nightly dosesof Xyrem® (2×2.25 g) provided much less total exposure to sodium oxybatewith a relative bioavailability of 67%.

TABLE 7e Pharmacokinetic Parameters of finished composition ofComparative Example 7 vs. Xyrem ® Mean C_(max) Mean AUC_(inf) MedianMean C_(8 h) (μg/mL) (h * μg/mL) T_(max) (hour) (μg/mL) (% CV) (% CV)(min-max) (% CV) Finished 28.99 (45) 143.90 (53) 1.5 (0.5-8) 7.79 (82) composition of Comparative Example 7 4.5 g Xyrem ® 1st dose: 214.32 (48)1st dose: 9.24 (127) 2 × 2.25 g 33.41 (41) 1.0 (0.5-2) 2nd dose: 2nddose: 65.91 (40) 4.5 (4.33-6.5)

TABLE 7f Mean plasma concentration (microgram/mL) of gamma-hydroxybutyrate versus time of finished composition of ComparativeExample 7 and Xyrem ® Comparative Comparative Example ExampleComparative 7 @ 4.5 g 7 @ 6.0 g Example Xyrem ® (2 h after meal) (2 hafter meal) 7 @ 7.5 g (2 × 2.25 g) Time pooled mean pooled mean (2 hafter part I (hour) (N = 27) (N = 18) meal) (N = 12) (N = 15) 0 0.000.00 0.00 0.00 0.5 18.84 25.54 31.40 27.44 1 23.93 35.80 46.78 28.97 1.524.31 38.59 58.29 26.12 2 24.32 40.78 57.47 21.11 2.5 23.10 38.03 52.2513.93 3 20.05 35.76 49.00 10.25 3.5 17.47 33.99 45.66 6.92 4 16.48 30.4740.52 0.00 4.5 15.44 26.87 37.70 57.33 5 14.10 25.59 36.82 52.27 5.512.60 24.63 35.93 43.55 6 11.68 23.90 34.47 35.20 6.5 11.45 23.98 31.6027.44 7 10.64 20.94 31.89 19.36 7.5 9.35 17.93 29.69 13.88 8 7.79 14.3625.80 9.24 10 1.98 3.71 11.00 2.64 12 0.59 0.78 3.63 NC NC: notcalculated

The pharmacokinetic profiles of single 6 g and 7.5 g doses of thefinished composition produced according to comparative Example 7 werealso generated. Table 7g provides data on a single 4.5 g, 6 g and 7.5 gdose, showing effects on C_(max), C_(8h), AUC_(8h) and AUC_(inf) relatedto dose strength.

TABLE 7g Pharmacokinetic Parameters of 4.5 g, 6 g, and 7.5 g of finishedcomposition produced according Comparative Example 7 Finished Mean MeanMedian T_(max) composition Mean C_(max) AUC_(inf) AUC_(8 h) (min-max)Mean C_(8 h) Comparative of (μg/mL) (h * μg/mL) (h * μg/mL) (h) (μg/mL)Example 7 (% CV) (% CV) (% CV) (% CV) (% CV) 4.5 g 28.98 (45) 143.90(53) 128.83 (55) 1.5 (0.5-8)  7.79 (82)   6 g 45.64 (35) 248.24 (47)225.00 (47)    2 (0.5-6.5) 14.36 (77) 7.5 g 63.31 (33) 379.83 (54)316.18 (48) 1.75 (1-4.5)  25.80 (74)

Example 8. Alternative Formulations Example 8.1: Modified ReleaseFormulation of Gamma-Hydroxybutyrate Comprising Immediate ReleaseMicroparticles of Potassium Salt of Gamma-Hydroxybutyric Acid andModified Release Microparticles of Sodium Salt of Gamma-HydroxybutyricAcid (Sodium Oxybate)

Immediate release (IR) microparticles of potassium salt ofgamma-hydroxybutyric acid can be prepared as follows: 1615.0 g ofpotassium salt of gamma-hydroxybutyric acid and 85.0 g ofpolyvinylpyrrolidone (Povidone K30—Plasdone™ K29/32 from ISP) aresolubilized in 1894.3 g of absolute ethyl alcohol and 1262.9 g of water.The solution is entirely sprayed onto 300 g of microcrystallinecellulose spheres (Cellets™ 127) in a fluid bed spray coater apparatus.

Immediate release (IR) microparticles of sodium salt ofgamma-hydroxybutyric acid were prepared as follows: 1615.0 g of sodiumsalt of gamma-hydroxybutyric acid and 85.0 g of polyvinylpyrrolidone(Povidone K30—Plasdone K29/32 from ISP) were solubilized in 1894.3 g ofabsolute ethyl alcohol and 1262.9 g of water. The solution was entirelysprayed onto 300 g of microcrystalline cellulose spheres (Cellets™ 127from Pharmatrans Sanaq) in a fluid bed spray coater apparatus.

Sodium oxybate modified release (MR) microparticles are prepared asfollows: 22.8 g of methacrylic acid copolymer Type C (Eudragit™L100-55), 45.8 g of methacrylic acid copolymer Type B (Eudragit™ S100),102.9 g of hydrogenated cottonseed oil (Lubritab™), are dissolved in1542.9 g of isopropanol at 78° C. The solution is sprayed entirely onto400.0 g of the sodium oxybate IR microparticles described above in afluid bed spray coater apparatus with an inlet temperature of 48° C.,spraying rate around 11 g per min and atomization pressure of 1.3 bar.MR microparticles are dried for two hours with inlet temperature set to56° C. MR microparticles with mean volume diameter of about 320 micronswere obtained.

The finished formulation, which contains a 50:50 mixture of MR and IRmicroparticles calculated on their gamma-hydroxybutyrate content, can beprepared as follows: 398.51 g of the above IR microparticles, 504.80 gof the above MR microparticles, 16.09 g of D/L malic acid, 6.34 g ofxanthan gum (Xantural™ 75 from Kelco), 9.51 g of carrageenan gum(Viscarin™ PH209 from FMC Biopolymer), 9.51 g of hydroxyethylcellulose(Natrosol™ 250M from Ashland) and 4.75 g of magnesium stearate weremixed. Individual samples of 7.49 g of the mixture (amount equivalent toa 4.5 g dose of sodium oxybate with half of the dose asimmediate-release fraction and half of the dose as modified releasefraction) were weighed.

TABLE 8a Composition of IR Microparticles of gamma-hydroxybutyrate ofexample 8.1 Quantity per 2.25 g Component Function dose (g) Potassiumsalt of hydroxybutyric acid Drug substance 2.537 Microcrystallinecellulose spheres Core 0.471 Povidone K30 Binder and excipient 0.134 indiffusion coating Ethyl alcohol Solvent Eliminated during processingPurified water Solvent Eliminated during processing Total 3.142

TABLE 8b Composition of MR Microparticles of gamma-hydroxybutyrate ofexample 8.1 Quantity per 2.25 g Component Function dose (g) Sodiumoxybate Drug substance 2.25  Povidone K30 Binder 0.118 Microcrystallinecellulose spheres Core 0.419 Hydrogenated Vegetable Oil Coatingexcipient 0.717 Methacrylic acid Copolymer Coating excipient 0.159 TypeC Methacrylic acid Copolymer Coating excipient 0.318 Type B Ethylalcohol Solvent Eliminated during processing Acetone Solvent Eliminatedduring processing Water Solvent Eliminated during processing Isopropylalcohol Solvent Eliminated during processing Total 3.981

TABLE 8c Qualitative Composition of Finished Formulation of Example 8.1Quantity per Component Function 4.5 g dose (g) MR microparticlesModified release fraction of 3.981 sodium oxybate IR microparticlesImmediate release fraction 3.142 of potassium salt ofgamma-hydroxybutyric acid Malic acid Acidifying agent 0.127 Xanthan gumSuspending agent 0.050 Hydroxyethylcellulose Suspending agent 0.075Carrageenan gum Suspending agent 0.075 Magnesium stearate Lubricant0.037 Total 7.487

TABLE 8d Quantitative Composition of Finished Formulation of Example 8.1Quantity per Component Function 4.5 g dose (g) Sodium oxybate Drugsubstance 2.25 Potassium salt of gamma- Drug substance 2.537hydroxybutyric acid Microcrystalline cellulose spheres Core 0.890Povidone K30 Binder 0.252 Hydrogenated Vegetable Oil Coating excipient0.717 Methacrylic acid Copolymer Type C Coating excipient 0.159Methacrylic acid Copolymer Type B Coating excipient 0.318 Malic acidAcidifying agent 0.127 Xanthan gum Suspending agent 0.050Hydroxyethylcellulose Suspending agent 0.075 Carrageenan gum Suspendingagent 0.075 Magnesium stearate Lubricant 0.037 Total 7.487

Example 8.2: Modified Release Formulation of Gamma-HydroxybutyrateComprising Immediate Release Microparticles of Potassium Salt ofGamma-Hydroxybutyric Acid, Immediate Release Microparticles of MagnesiumSalt of Gamma-Hydroxybutyric Acid, Immediate Release Microparticles ofCalcium Salt of Gamma-Hydroxybutyric Acid and Modified ReleaseMicroparticles of Sodium Salt of Gamma-Hydroxybutyric Acid (SodiumOxybate)

Immediate release (IR) microparticles of potassium salt ofgamma-hydroxybutyric acid are prepared according to example 8.1.

Immediate release (IR) microparticles of magnesium salt ofgamma-hydroxybutyric acid or calcium salt of gamma-hydroxybutyric acidcan be prepared using the same manufacturing process by replacing thepotassium salt of gamma-hydroxybutyric acid by the same weight ofrespectively magnesium salt of gamma-hydroxybutyric acid or calcium saltof gamma-hydroxybutyric acid.

Sodium oxybate modified release (MR) microparticles are preparedaccording to example 8.1.

The finished formulation, which contains a 50:50 mixture of MR and IRmicroparticles calculated on their gamma-hydroxybutyrate content, can beprepared as follows: 132.84 g of the IR microparticles of potassium saltof gamma-hydroxybutyric acid, 215.32 g of the IR microparticles ofmagnesium salt of gamma-hydroxybutyric acid, 230.05 g of the IRmicroparticles of calcium salt of gamma-hydroxybutyric acid, 504.80 g ofthe MR microparticles of sodium oxybate, 23.35 g of D/L malic acid, 6.34g of xanthan gum (Xantural™ 75 from Kelco), 9.51 g of carrageenan gum(Viscarin™ PH209 from FMC Biopolymer), 9.51 g of hydroxyethylcellulose(Natrosol™ 250M from Ashland) and 5.69 g of magnesium stearate weremixed. Individual samples of 8.96 g of the mixture (amount equivalent toa 4.5 g dose of sodium oxybate with half of the dose asimmediate-release fraction and half of the dose as modified releasefraction) were weighed.

TABLE 8e Qualitative Composition of Finished Formulation of Example 8.2Quantity per 4.5 g Component Function dose (g) MR microparticlesModified release fraction of 3.981 sodium oxybate IR microparticlesImmediate release fraction of 4.559 potassium salt of gamma-hydroxybutyric acid + immediate release fraction of magnesium salt ofgamma-hydroxybutyric acid + immediate release fraction of calcium saltof gamma-hydroxybutyric acid Malic acid Acidifying agent 0.184 Xanthangum Suspending agent 0.050 Hydroxyethylcellulose Suspending agent 0.075Carrageenan gum Suspending agent 0.075 Magnesium stearate Lubricant0.045 Total 8.97

TABLE 8f Quantitative Composition of Finished Formulation of Example 8.2Quantity per Component Function 4.5 g dose (g) Sodium oxybate Drugsubstance 2.25 Potassium salt of gamma- Drug substance 0.84hydroxybutyric acid Magnesium salt of gamma- Drug substance 1.37hydroxybutyric acid Calcium salt of gamma- Drug substance 1.46hydroxybutyric acid Microcrystalline cellulose spheres Core 1.102Povidone K30 Binder 0.312 Hydrogenated Vegetable Oil Coating excipient0.717 Methacrylic acid Copolymer Type C Coating excipient 0.159Methacrylic acid Copolymer Type B Coating excipient 0.318 Malic acidAcidifying agent 0.184 Xanthan gum Suspending agent 0.050Hydroxyethylcellulose Suspending agent 0.075 Carrageenan gum Suspendingagent 0.075 Magnesium stearate Lubricant 0.045 Total 8.96

Example 8.3: Modified Release Formulation of Gamma-HydroxybutyrateComprising Immediate Release Microparticles of Potassium Salt ofGamma-Hydroxybutyric Acid and Modified Release Microparticles of CalciumSalt of Gamma-Hydroxybutyric Acid

Immediate release (IR) microparticles of potassium salt ofgamma-hydroxybutyric acid are prepared according to example 8.1.

Immediate release (IR) microparticles of calcium salt ofgamma-hydroxybutyric acid can be prepared using the manufacturingprocess described in example 8.1 for immediate release (IR)microparticles of potassium salt of gamma-hydroxybutyric acid byreplacing the potassium salt of gamma-hydroxybutyric acid by the sameweight of calcium salt of gamma-hydroxybutyric acid. These Immediaterelease (IR) microparticles of calcium salt of gamma-hydroxybutyric acidare used to manufacture modified release (MR) microparticles of calciumsalt of gamma-hydroxybutyric acid as follows: 22.8 g of methacrylic acidcopolymer Type C (Eudragit™ L100-55), 45.8 g of methacrylic acidcopolymer Type B (Eudragit™ S100), 102.9 g of hydrogenated cottonseedoil (Lubritab™), are dissolved in 1542.9 g of isopropanol at 78° C. Thesolution is sprayed entirely onto 400.0 g of the immediate releasemicroparticles of calcium salt of gamma-hydroxybutyric acid describedabove in a fluid bed spray coater apparatus with an inlet temperature of48° C., spraying rate around 11 g per min and atomization pressure of1.3 bar. MR microparticles are dried for two hours with inlettemperature set to 56° C.

The finished formulation, which contains a 50:50 mixture of MR and IRmicroparticles calculated on their gamma-hydroxybutyrate content, can beprepared as follows: 398.53 g of the IR microparticles of potassium saltof gamma-hydroxybutyric acid, 492.87 g of the MR microparticles ofsodium oxybate, 16.10 g of D/L malic acid, 6.34 g of xanthan gum(Xantural™ 75 from Kelco), 9.51 g of carrageenan gum (Viscarin™ PH209from FMC Biopolymer), 9.51 g of hydroxyethylcellulose (Natrosol™ 250Mfrom Ashland) and 4.69 g of magnesium stearate were mixed. Individualsamples of 7.39 g of the mixture (amount equivalent to a 4.5 g dose ofsodium oxybate with half of the dose as immediate-release fraction andhalf of the dose as modified release fraction) were weighed.

TABLE 8g Qualitative Composition of Finished Formulation of Example 8.3Quantity per Component Function 4.5 g dose (g) MR microparticlesModified release fraction 3.887 of calcium salt of gamma- hydroxybutyricacid IR microparticles Immediate release fraction of 3.143 potassiumsalt of gamma- hydroxybutyric acid Malic acid Acidifying agent 0.127Xanthan gum Suspending agent 0.050 Hydroxyethylcellulose Suspendingagent 0.075 Carrageenan gum Suspending agent 0.075 Magnesium stearateLubricant 0.037 Total 7.39

TABLE 8h Quantitative Composition of Finished Formulation of Example 8.3Quantity per Component Function 4.5 g dose (g) 7Potassium salt of gamma-Drug substance 2.54 hydroxybutyric acid Calcium salt of gamma- Drugsubstance 2.19 hydroxybutyric acid Microcrystalline cellulose spheresCore 0.880 Povidone K30 Binder 0.249 Hydrogenated Vegetable Oil Coatingexcipient 0.700 Methacrylic acid Copolymer Type C Coating excipient0.155 Methacrylic acid Copolymer Type B Coating excipient 0.311 Malicacid Acidifying agent 0.127 Xanthan gum Suspending agent 0.050Hydroxyethylcellulose Suspending agent 0.075 Carrageenan gum Suspendingagent 0.075 Magnesium stearate Lubricant 0.037 Total 7.39

Example 9: Alternative Formulations with Differing Concentrations ofAcidic Agents

Different prototypes were developed to evaluate the effect of acidicagent on the dissolution stability of the formulation dispersed inwater. Experimental data with 0.8%, 1.6% and 15% malic acid are detailedbelow.

Example 9.1: 1.6% Malic Acid

IR particles were prepared as follows: 1615.0 g of Sodium Oxybate and85.0 g of water soluble polymer polyvinylpyrrolidone (Povidone—Plasdone™K30 from ISP) were solubilized in 1894.3 g of absolute ethyl alcohol and1262.9 g of water. The solution was entirely sprayed onto 300 g ofmicrocrystalline cellulose spheres (Cellets™ 127 from Pharmatrans) in afluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particleswith mean diameter of 268 microns were obtained.

MR coated particles were prepared as follows: 39.9 g of Methacrylic acidcopolymer Type C (Eudragit™ L100-55 from Evonik), 80.1 g of Methacrylicacid copolymer Type B (Eudragit™ S100 from Evonik), 180.0 g ofHydrogenated cottonseed oil (Lubritab™ from JRS), were dissolved in2700.0 g of isopropanol at 78° C. The solution was sprayed entirely on700.0 g of IR particles in a fluid bed spray coater apparatus Glatt™G.P.C.G.1.1 with inlet temperature 49° C., spraying rate around 11.6 gper min and atomization pressure 1.6 bar. MR microparticles were driedfor 2 hours with inlet temperature set to 56° C. Sodium oxybate MRcoated particles with mean diameter of 324 microns were obtained.

The finished composition, which contains a 50:50 mixture of MR and IRparticles calculated on their sodium oxybate content, was prepared asfollows: 655.1 g of the above IR particles, 936.4 g of the above MRparticles, 26.5 g of Malic acid (D/L malic acid regular from Bartek),11.7 g of xanthan gum (Xantural™ 75 from CP Kelco), 17.6 g ofcarrageenan gum (Viscarin™ PH209 from FMC Biopolymer), 17.6 g ofhydroxyethylcellulose (Natrosol™ 250M from Ashland) and 8.2 g ofmagnesium stearate (from Peter Greven) were mixed in a Roue-Roehn mixer.Individual doses of 7.11 g (corresponding to a 4.5 g dose with half ofthe dose as immediate-release fraction and half of the dose as modifiedrelease fraction) were weighed.

FIG. 29 and Table 9a below depict dissolution profiles determined in0.1N HCl using a USP apparatus 2. The dissolution medium was maintainedat 37.0±0.5° C. and the rotating paddle speed was fixed at 75 rpm.Single dose units were poured in a container containing 50 mL of tapwater. After 5 and 15 minutes, the suspension was poured in thedissolution vessel containing 840 mL of 0.1N HCl dissolution medium. 10mL of water were used to rinse the container and were added to thedissolution vessel.

TABLE 9a % dissolved % dissolved Time (h) 5 min reconstitution time 15min reconstitution time 0 0 0 0.25 47 48 1 53 52 3 53 53 6 55 54 8 59 6010 74 77 12 87 88 16 96 97 20 97 98

Example 9.2: 0.8% Malic Acid

IR particles were prepared as follows: 1615.0 g of Sodium Oxybate and85.0 g of water soluble polymer polyvinylpyrrolidone (Povidone—Plasdone™K30 from ISP) were solubilized in 1894.3 g of absolute ethyl alcohol and1262.9 g of water. The solution was entirely sprayed onto 300 g ofmicrocrystalline cellulose spheres (Cellets™ 127 from Pharmatrans) in afluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particleswith mean diameter of 273 microns were obtained.

MR coated particles were prepared as follows: 39.9 g of Methacrylic acidcopolymer Type C (Eudragit™ L100-55 from Evonik), 80.1 g of Methacrylicacid copolymer Type B (Eudragit™ S100 from Evonik), 180.0 g ofHydrogenated cottonseed oil (Lubritab™ from JRS), were dissolved in2700.0 g of isopropanol at 78° C. The solution was sprayed entirely on700.0 g of IR particles in a fluid bed spray coater apparatus Glatt™G.P.C.G.1.1 with inlet temperature 47° C., spraying rate around 10.7 gper min and atomization pressure 1.6 bar. MR microparticles were driedfor 2 hours with inlet temperature set to 60° C. Sodium oxybate MRcoated particles with mean diameter of 309 microns were obtained.

The finished composition, which contains a 50:50 mixture of MR and IRparticles calculated on their sodium oxybate content, was prepared asfollows: 100.0 g of the above IR particles, 142.9 g of the above MRparticles, 2.0 g of Malic acid (D/L malic acid regular from Bartek), 1.2g of xanthan gum (Xantural™ 75 from CP Kelco), 1.2 g of hydrophilicfumed silica (Aerosil™ 200 from Degussa) and 2.5 g of magnesium stearate(from Peter Greven) were mixed in a Roue-Roehn mixer. Individual dosesof 6.93 g (corresponding to a 4.5 g dose with half of the dose asimmediate-release fraction and half of the dose as modified releasefraction) were weighed.

FIG. 30 and Table 9b below depict dissolution profiles determined in0.1N HCl using a USP apparatus 2. The dissolution medium was maintainedat 37.0±0.5° C. and the rotating paddle speed was fixed at 75 rpm.Single dose units were poured in a container containing 50 mL of tapwater. After 5 and 15 minutes, the suspension was poured in thedissolution vessel containing 840 mL of 0.1N HCl dissolution medium. 10mL of water were used to rinse the container and were added to thedissolution vessel.

TABLE 9b % dissolved % dissolved Time (h) 5 min reconstitution time 15min reconstitution time 0 0 0 0.25 51 51 1 51 52 3 51 53 6 52 62 8 60 8610 77 96 12 90 98 16 98 98

Example 9.3: 15% Malic Acid

IR particles were prepared as follows: 1615.0 g of Sodium Oxybate and85.0 g of water soluble polymer polyvinylpyrrolidone (Povidone—Plasdone™K30 from ISP) were solubilized in 1894.3 g of absolute ethyl alcohol and1262.9 g of water. The solution was entirely sprayed onto 300 g ofmicrocrystalline cellulose spheres (Cellets™ 127 from Pharmatrans) in afluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particleswith mean diameter of 255 microns were obtained.

MR coated particles were prepared as follows: 22.8 g of Methacrylic acidcopolymer Type C (Eudragit™ L100-55 from Evonik), 45.8 g of Methacrylicacid copolymer Type B (Eudragit™ S100 from Evonik), 102.9 g ofHydrogenated cottonseed oil (Lubritab™ from JRS), were dissolved in1544.8 g of isopropanol at 78° C. The solution was sprayed entirely on400.0 g of IR particles in a fluid bed spray coater apparatus Glatt™G.P.C.G.1.1 with inlet temperature 49° C., spraying rate around 12.0 gper min and atomization pressure 1.3 bar. MR microparticles were driedfor 2 hours with inlet temperature set to 56° C. Sodium oxybate MRcoated particles with mean diameter of 298 microns were obtained.

The finished composition, which contains a 50:50 mixture of MR and IRparticles calculated on their sodium oxybate content, was prepared asfollows: 36.2 g of the above IR particles, 51.8 g of the above MRparticles, 16.1 g of Malic acid (D/L malic acid regular from Bartek),0.7 g of xanthan gum (Xantural™ 75 from CP Kelco), 1.0 g of carrageenangum (Viscarin™ PH209 from FMC Biopolymer), 1.0 g ofhydroxyethylcellulose (Natrosol™ 250M from Ashland) and 0.6 g ofmagnesium stearate (from Peter Greven) were mixed in a Roue-Roehn mixer.Individual doses of 8.25 g (corresponding to a 4.5 g dose with half ofthe dose as immediate-release fraction and half of the dose as modifiedrelease fraction) were weighed.

FIG. 31 and Table 9c below depict dissolution profiles determined in0.1N HCl using a USP apparatus 2. The dissolution medium was maintainedat 37.0±0.5° C. and the rotating paddle speed was fixed at 75 rpm.Single dose units were poured in a container containing 50 mL of tapwater. After 5 and 15 minutes, the suspension was poured in thedissolution vessel containing 840 mL of 0.1N HCl dissolution medium. 10mL of water were used to rinse the container and were added to thedissolution vessel.

TABLE 9c % dissolved % dissolved Time (h) 5 min reconstitution time 15min reconstitution time 0 0 0 0.25 48 49 1 51 51 3 51 51 4 51 51 6 52 518 56 56 10 71 71 12 86 85 16 97 96 20 99 98

Example 10. Alternative Formulations

Suspending agents are present in the formulation to limit microparticlessettling after reconstitution. Without suspending agents, microparticlesstarts settling as soon as shaking stops. In presence of the suspendingagents, full microparticles settling does not occur in less than 1minute. The following data illustrates the good pourability of thesuspension assessed by the high recovery of sodium oxybate content inthe dissolution test:

IR particles were prepared as follows: 1615.0 g of sodium oxybate and85.0 g of water soluble polymer polyvinylpyrrolidone (Povidone—Plasdone™K30 from ISP) were solubilized in 1894.3 g of absolute ethyl alcohol and1262.9 g of water. The solution was entirely sprayed onto 300 g ofmicrocrystalline cellulose spheres (Cellets™ 127 from Pharmatrans) in afluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particleswith mean diameter of 271 microns were obtained.

MR coated particles were prepared as follows: 39.9 g of methacrylic acidcopolymer type C (Eudragit™ L100-55 from Evonik), 80.1 g of methacrylicacid copolymer type B (Eudragit™ S100 from Evonik), 180.0 g ofhydrogenated cottonseed oil (Lubritab™ from JRS), were dissolved in2700.0 g of isopropanol at 78° C. The solution was sprayed entirely on700.0 g of sodium oxybate IR particles in a fluid bed spray coaterapparatus Glatt™ G.P.C.G.1.1 with inlet temperature 48° C., sprayingrate around 11.5 g per min and atomization pressure 1.6 bar. MR coatedparticles were dried for 2 hours with inlet temperature set to 56° C. MRparticles of sodium oxybate with mean diameter of 321 microns wereobtained.

The finished composition, which contains a 50:50 mixture of MR and IRsodium oxybate particles calculated on their sodium oxybate content, wasprepared as follows: 634.0 g of the above IR particles, 907.6 g of theabove MR particles, 25.7 g of malic acid (D/L malic acid regular fromBartek), 11.4 g of xanthan gum (Xantural™ 75 from CP Kelco), 17.1 g ofcarrageenan gum (Viscarin™ PH209 from FMC Biopolymer), 17.1 g ofhydroxyethylcellulose (Natrosol™ 250M from Ashland) and 8.1 g ofmagnesium stearate (from Peter Greven) were mixed in a Roue-Roehn mixer.Individual doses of 14.20 g (corresponding to a 9 g dose with half ofthe dose as immediate-release fraction and half of the dose as modifiedrelease fraction) were weighed.

FIG. 32 and Table 10a below depict dissolution profiles of 9 g dosesdetermined using a USP apparatus 2 in 0.1N HCl. The dissolution mediumwas maintained at 37.0±0.5° C. and the rotating paddle speed was fixedat 75 rpm. Single dose units were poured in a container containing 50 mLof tap water. After 5 minutes, the suspension was poured in thedissolution vessel containing 840 mL of 0.1N HCl dissolution medium. 10mL of water were used to rinse the container and were added to thedissolution vessel. Dissolution profile was determined with and withoutrinsing step.

TABLE 10a Time (h) with rinsing without rinsing 0 0 0 0.25 47 46 1 51 513 53 52 6.0 54 53 8 61 60 10 77 74 12 91 88 16 98 95 20 98 96

Example 11. Alternative Formulations with a Different Ratio of IR and MRFractions

Different prototypes were prepared and evaluated to determine the effectof IR/MR ratio.

Example 11a: 15% IR/85% IR with MR pH*6.5 Microparticles

IR particles were prepared as follows: 1615.0 g of Sodium Oxybate and85.0 g of water soluble polymer polyvinylpyrrolidone (Povidone—Plasdone™K30 from ISP) were solubilized in 1896.2 g of absolute ethyl alcohol and1264.4 g of water. The solution was entirely sprayed onto 300 g ofmicrocrystalline cellulose spheres (Cellets™ 127 from Pharmatrans) in afluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particleswith mean diameter of 275 microns were obtained.

MR coated particles were prepared as follows: 22.8 g of Methacrylic acidcopolymer Type C (Eudragit™ L100-55 from Evonik), 45.8 g of Methacrylicacid copolymer Type B (Eudragit™ S100 from Evonik), 102.9 g ofHydrogenated cottonseed oil (Lubritab™ from JRS), were dissolved in1543.1 g of isopropanol at 78° C. The solution was sprayed entirely on400.0 g of IR particles in a fluid bed spray coater apparatus Glatt™G.P.C.G.1.1 with inlet temperature 47° C., spraying rate around 10.8 gper min and atomization pressure 1.3 bar. MR microparticles were driedfor 2 hours with inlet temperature set to 56° C. Sodium oxybate MRcoated particles with mean diameter of 330 microns were obtained.

17.1 g of MR microparticles were mixed with 0.09 g of magnesium stearate(from Peter Greven). The dissolution profile of 4000 mg of the mixturewhich correspond to 2250 mg of sodium oxybate per vessel was determinedin 900 ml of 0.1N HCl and pH 6.8 phosphate buffer (0.05M monobasicpotassium phosphate solution—pH adjusted to 6.8 with 5N NaOH) using theUSP apparatus 2. Dissolution medium temperature was maintained at37.0±0.5° C., and the rotating paddle speed was set at 75 rpm. Therelease profiles are shown in FIG. 33, Table 11a, and Table 11b.

TABLE 11a Dissolution data - 0.1N HCl Time (hour) % dissolved 0 0.0 0.251 1 1 3 2 4 3 6 6 8 24 10 59 12 83 16 95 20 97

TABLE 11b Dissolution data - 50 mM phosphate buffer pH 6.8 Time (hour) %dissolved 0 0 0.25 18 0.5 80 0.75 97 1 97 2 97

The qualitative composition of 4.5 g dose units comprising 15% of thedose as IR fraction and 85% of the dose as MR fraction is described inTable 11c.

TABLE 11c Quantity per Component Function 4.5 g dose (g) MRmicroparticles Modified release fraction 6.767 of sodium oxybate IRmicroparticles Immediate release 0.836 fraction of sodium oxybate Malicacid Acidifying agent 0.034 Xanthan gum Suspending agent 0.050Hydroxyethylcellulose Suspending agent 0.075 Carrageenan gum Suspendingagent 0.075 Magnesium stearate Lubricant 0.039 Total 7.876

The finished composition, which contains a 85:15 mixture of MR and IRparticles calculated on their sodium oxybate content, can be prepared asfollows: 100.0 g of the above IR particles, 809.5 g of the above MRparticles, 4.0 g of malic acid (D/L malic acid regular from Bartek), 6.0g of xanthan gum (Xantural™ 75 from CP Kelco), 9.0 g of carrageenan gum(Viscarin™ PH209 from FMC Biopolymer), 9.0 g of hydroxyethylcellulose(Natrosol™ 250M from Ashland) and 4.7 g of magnesium stearate (fromPeter Greven) were mixed in a Roue-Roehn mixer. Individual doses of 7.88g (corresponding to a 4.5 g dose with 15% of the dose asimmediate-release fraction and 85% of the dose as modified releasefraction) were weighed.

After reconstitution with 50 ml of tap water and a rinsing volume of 10ml of tap water, the finished composition will display the dissolutionprofiles in FIGS. 34 and 35 and Tables 11d and 11e in 840 ml of 0.1N HCland in pH6.8 phosphate buffer (0.05M monobasic potassium phosphatesolution—pH adjusted to 6.8 with 5N NaOH) using a USP apparatus 2, at37.0±0.5° C. and the rotating paddle speed at 75 rpm.

TABLE 11d Time (hour) % dissolved 0 0.0 0.25 16 1 16 3 17 4 17 6 20 8 3510 65 12 85 16 96

TABLE 11e Time (hour) % dissolved 0 0 0.25 30 0.5 83 0.75 97 1 98 2 98

Example 11B 30% IR/70% MR with MR pH*6.2 Microparticles

IR particles were prepared as follows: 1615.1 g of sodium oxybate and85.0 g of water soluble polymer polyvinylpyrrolidone (Povidone—Plasdone™K30 from ISP) were solubilized in 1903.2 g of absolute ethyl alcohol and1267.1 g of water. The solution was entirely sprayed onto 300 g ofmicrocrystalline cellulose spheres (Cellets™ 127 from Pharmatrans) in afluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particleswith mean diameter of 268 microns were obtained.

MR coated particles were prepared as follows: 36.6 g of Methacrylic acidcopolymer Type C (Eudragit™ L100-55 from Evonik), 32.1 g of methacrylicacid copolymer type B (Eudragit™ S100 from Evonik), 103.0 g ofhydrogenated cottonseed oil (Lubritab™ from JRS), were dissolved in1543.5 g of isopropanol at 78° C. The solution was sprayed entirely on400.0 g of IR particles in a fluid bed spray coater apparatus Glatt™G.P.C.G.1.1 with inlet temperature 48° C., spraying rate around 12.0 gper min and atomization pressure 1.3 bar. MR particles were dried for 2hours with inlet temperature set to 56° C. Sodium oxybate MR coatedparticles with mean diameter of 323 microns were obtained.

17.0 g of sodium oxybate MR particles were mixed with 0.09 g ofmagnesium stearate (from Peter Greven). The dissolution profile of 4050mg of the mixture which correspond to 2280 mg of sodium oxybate pervessel was determined in 900 ml of 0.1N HCl dissolution medium using theUSP apparatus 2. Dissolution medium temperature was maintained at37.0±0.5° C., and the rotating paddle speed was set at 75 rpm. Therelease profile in 0.1N HCl is shown in FIG. 36 and Table 11f.

TABLE 11f Time (hour) % dissolved 0.0 0 0.3 1 1.0 3 3.0 4 4.0 4 6.0 88.0 40 10.0 81 12.0 95 16.0 100 20.0 99

The finished composition, which contains a 70:30 mixture of MR and IRsodium oxybate particles calculated on their sodium oxybate content, wasprepared as follows: 92.1 g of the above IR particles, 306.5 g of theabove MR particles, 7.5 g of malic acid (D/L malic acid regular fromBartek), 2.8 g of xanthan gum (Xantural™ 75 from CP Kelco), 4.1 g ofcarrageenan gum (Viscarin™ PH209 from FMC Biopolymer), 4.1 g ofhydroxyethylcellulose (Natrosol™ 250M from Ashland) and 2.0 g ofmagnesium stearate (from Peter Greven) were mixed in a Roue-Roehn mixer.Individual doses of 7.62 g (corresponding to a 4.5 g dose with 30% ofthe dose as immediate-release fraction and 70% of the dose as modifiedrelease fraction) were weighed.

FIGS. 37 and 38 and Tables 11g and 11h below depict dissolution profilesdetermined using a USP apparatus 2 in 0.1N HCl and pH 6.8 phosphatebuffer (0.05M monobasic potassium phosphate solution—pH adjusted to 6.8with 5N NaOH). The dissolution medium was maintained at 37.0±0.5° C. andthe rotating paddle speed was fixed at 75 rpm. Single dose units werepoured in a container containing 50 mL of tap water. After 5 minutes,the suspension was poured in the dissolution vessel containing 840 mL ofdissolution medium. 10 mL of water were used to rinse the container andwere added to the dissolution vessel.

TABLE 11g Time (hour) % dissolved in 0.1N HCl 0.0 0.0 0.3 29 1.0 31 3.032 4.0 32 6.0 35 8.0 70 10.0 94 12.0 99 16.0 99

TABLE 11h Time (h) % dissolved in pH 6.8 phosphate buffer 0 0 0.25 640.5 87 1 100 2 100 3 102

Example 11c: 65% IR/35% MR with MR pH*6.5 Microparticles

IR particles were prepared as follows: 1615.0 g of sodium oxybate and85.0 g of water soluble polymer polyvinylpyrrolidone (Povidone—Plasdone™K30 from ISP) were solubilized in 1894.3 g of absolute ethyl alcohol and1262.9 g of water. The solution was entirely sprayed onto 300 g ofmicrocrystalline cellulose spheres (Cellets™ 127 from Pharmatrans) in afluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particleswith mean diameter of 270 microns were obtained.

MR coated particles were prepared as follows: 22.8 g of methacrylic acidcopolymer type C (Eudragit™ L100-55 from Evonik), 45.8 g of methacrylicacid copolymer type B (Eudragit™ S100 from Evonik), 102.9 g ofhydrogenated cottonseed oil (Lubritab™ from JRS), were dissolved in1543.1 g of isopropanol at 78° C. The solution was sprayed entirely on400.0 g of IR particles in a fluid bed spray coater apparatus Glatt™G.P.C.G.1.1 with inlet temperature 47° C., spraying rate around 10.8 gper min and atomization pressure 1.3 bar. MR coated particles were driedfor 2 hours with inlet temperature set to 56° C. Sodium oxybate MRcoated particles with mean diameter of 330 microns were obtained.

Refer to the Example 11a for the dissolution profile of the MRmicroparticles. The qualitative composition of 4.5 g dose unitscomprising 65% of the dose as IR fraction and 35% of the dose as MRfraction is described in Table 11i.

TABLE 11i Quantity per Component Function 4.5 g dose (g) MRmicroparticles Modified release fraction 2.786 of sodium oxybate IRmicroparticles Immediate release 3.622 fraction of sodium oxybate Malicacid Acidifying agent 0.110 Xanthan gum Suspending agent 0.050Hydroxyethylcellulose Suspending agent 0.075 Carrageenan gum Suspendingagent 0.075 Magnesium stearate Lubricant 0.034 Total 6.752

The finished composition, which contains a 85:15 mixture of sodiumoxybate MR and IR particles calculated on their sodium oxybate content,can be prepared as follows: 100.0 g of the above IR particles, 76.9 g ofthe above MR coated particles, 3.0 g of Malic acid (D/L malic acidregular from Bartek), 1.4 g of xanthan gum (Xantural™ 75 from CP Kelco),2.1 g of carrageenan gum (Viscarin™ PH209 from FMC Biopolymer), 2.1 g ofhydroxyethylcellulose (Natrosol™ 250M from Ashland) and 0.9 g ofmagnesium stearate (from Peter Greven) were mixed in a Roue-Roehn mixer.Individual doses of 6.75 g (corresponding to a 4.5 g dose with 65% ofthe dose as immediate-release fraction and 35% of the dose as modifiedrelease fraction) were weighed.

Dissolution profile: After reconstitution with 50 ml tap water andrinsing with 10 ml of tap water, the finished composition will displaythe dissolution profiles in FIGS. 39 and 40 and Tables 11j and 11k in840 ml of 0.1N HCl and in pH 6.8 phosphate buffer (0.05M monobasicpotassium phosphate solution—pH adjusted to 6.8 with 5N NaOH) using aUSP apparatus 2, at 37.0±0.5° C. and the rotating paddle speed at 75rpm.

TABLE 11j Time (hour) % dissolved in 0.1N HCl 0 0.0 0.25 65 1 65 3 66 466 6 67 8 73 10 86 12 94 16 98 20 99

TABLE 11k Time (hour) % dissolved in pH 6.8 phosphate buffer 0 0 0.25 710.5 93 0.75 99 1 99 2 99

Example 12: Alternative Formulations with IR Fraction Obtained UsingDifferent Manufacturing Processes

Prototype formulations were developed to test the impact of differentmanufacturing processes on the dissolution of the formulations.

Example 12A: IR Portion=Raw Sodium Oxybate

IR particles to serve as cores of the MR coated microparticles wereprepared as follows: 1615.0 g of sodium oxybate and 85.0 g of watersoluble polymer polyvinylpyrrolidone (Povidone—Plasdone™ K30 from ISP)were solubilized in 1894.3 g of absolute ethyl alcohol and 1262.9 g ofwater. The solution was entirely sprayed onto 300 g of microcrystallinecellulose spheres (Cellets™ 127 from Pharmatrans) in a fluid bed spraycoater apparatus GPCG1.1. Sodium oxybate IR particles with mean diameterof 256 microns were obtained.

MR coated particles were prepared as follows: 22.8 g of methacrylic acidcopolymer type C (Eudragit™ L100-55 from Evonik), 45.8 g of methacrylicacid copolymer type B (Eudragit™ S100 from Evonik), 102.9 g ofhydrogenated cottonseed oil (Lubritab™ from JRS), were dissolved in1542.9 g of isopropanol at 78° C. The solution was sprayed entirely on400.0 g of IR particles in a fluid bed spray coater apparatus Glatt™G.P.C.G.1.1 with inlet temperature 48° C., spraying rate around 10 g permin and atomization pressure 1.3 bar. MR particles were dried for 2hours with inlet temperature set to 56° C. Sodium oxybate MR coatedparticles with mean diameter of 308 microns were obtained.

25.2 g of MR microparticles were mixed with 0.26 g of magnesium stearate(from Peter Greven) and 0.13 g of colloidal silicon dioxide (Aerosil™200 from Evonik). The dissolution profile of 4000 mg of the mixturewhich correspond to 2250 mg of sodium oxybate per vessel was determinedin 900 ml of 0.1N HCl dissolution medium using the USP apparatus 2.Dissolution medium temperature was maintained at 37.0±0.5° C., and therotating paddle speed was set at 75 rpm. The release profile in 0.1N HClis shown in FIG. 41 and Table 12a.

TABLE 12a Time (hour) % dissolved 0 0 0.25 1 1 1 3 2 4 3 6 14 8 40 10 6512 78 16 89

The finished composition, which contains a 50:50 mixture of sodiumoxybate MR coated particles and raw sodium oxybate as IR fractioncalculated on their sodium oxybate content, was prepared as follows: 36g of raw sodium oxybate, 63.7 g of the above MR coated particles, 1.8 gof malic acid (D/L malic acid regular from Bartek), 1.6 g of xanthan gum(Xantural™ 75 from CP Kelco), 2.4 g of carrageenan gum (Viscarin™ PH209from FMC Biopolymer), 0.047 g of an apple aroma and 0.3 g of hydrophilicfumed silica (Aerosil 200 from Degussa) were mixed in a Roue-Roehnmixer. Individual doses of 6.66 g (corresponding to a 4.5 g dose withhalf of the dose as raw sodium oxybate as IR fraction and half of thedose as modified release fraction) were weighed.

FIG. 42 and Table 12b below depict dissolution profiles determined usinga USP apparatus 2 in 0.1N HCl. The dissolution medium was maintained at37.0±0.5° C. and the rotating paddle speed was fixed at 75 rpm. Singledose units were poured in a container containing 50 mL of tap water.After 5 minutes, the suspension was poured in the dissolution vesselcontaining 840 mL of 0.1N HCl dissolution medium. 10 mL of water wereused to rinse the container and were added to the dissolution vessel.

TABLE 12b Time (hour) % dissolved 0 0 0.25 50 1 52 4 55 6 57 8 70 10 8212 87 16 93

Considering that the 0.1N HCl dissolution profile of the MR coatedparticles is similar to the MR microparticles from examples 1 and 1bis,the dissolution profile in pH 6.8 phosphate buffer of the finishedcomposition is expected to be similar to the profile depicted in FIG. 8,insofar as the MR particles are similar and only the nature of theimmediate-release fraction was changed.

Example 12B: IR=Microparticles Obtained by Extrusion-Spheronization

IR particles were prepared as follows: 97 g of sodium oxybate and 3 g ofwater soluble polymer polyvinylpyrrolidone (Povidone—Plasdone™ K30 fromISP) were mixed with 7.5 g of water. The mixture was extruded through a400 micron mesh and spheronized at 1500 rpm for 1.5 min in anextruder-spheronizer Fuji-Paudal MG-55. After drying for 4 hours at 45°C. in a ventilated oven, microparticles were sieved between 150 micronsand 500 microns.

MR coated particles were prepared as described in Example 14.

The finished composition, which contains a 50:50 mixture of MR and IRsodium oxybate particles calculated on their sodium oxybate content, wasprepared as follows: 67.4 g of the above IR particles obtained byextrusion-spheronization, 115.6 g of the above MR coated particles, 3.3g of malic acid (D/L malic acid regular from Bartek), 0.9 g of xanthangum (Xantural™ 75 from CP Kelco), 0.9 g of hydrophilic fumed silica(Aerosil 200 from Degussa) and 1.9 g of magnesium stearate (from PeterGreven) were mixed in a Roue-Roehn mixer. Individual doses of 6.54 g(corresponding to a 4.5 g dose with half of the dose asimmediate-release fraction and half of the dose as modified releasefraction) were weighed.

FIG. 43 and Table 12c below depict dissolution profiles determined usinga USP apparatus 2 in 0.1N HCl. The dissolution medium was maintained at37.0±0.5° C. and the rotating paddle speed was fixed at 75 rpm. Singledose units were poured in a container containing 50 mL of tap water.After 5 minutes, the suspension was poured in the dissolution vesselcontaining 840 mL of 0.1N HCl dissolution medium. 10 mL of water wereused to rinse the container and were added to the dissolution vessel.

TABLE 12c Time (hour) % dissolved in 0.1N HCl 0 0 0.25 51 1 53 4 54 6 548 56 10 65 12 79 16 92

Based on the dissolution profile of the MR coated particles in pH 6.8phosphate buffer, finished compositions are expected to have thedissolution profile in pH 6.8 phosphate buffer given in Table 12d andFIG. 44.

TABLE 12d Time (h) % dissolved in pH 6.8 phosphate buffer 0 0 0.25 550.50 97 1 101 1.5 102 2 101 3 101

Example 13. Alternative Formulation without Binder

IR particles were prepared as follows: 1700.0 g of Sodium Oxybate aresolubilized in 1899.4 g of absolute ethyl alcohol and 1261.3 g of water.The solution is entirely sprayed onto 300 g of microcrystallinecellulose spheres (Cellets 127 from Pharmatrans) in a fluid bed spraycoater apparatus GPCG1.1. Sodium oxybate IR particles with mean diameterof 244 microns are obtained.

MR coated particles were prepared as follows: 17.1 g of methacrylic acidcopolymer type C (Eudragit L100-55 from Evonik), 34.3 g of methacrylicacid copolymer type B (Eudragit S100 from Evonik), 77.1 g ofhydrogenated cottonseed oil (Lubritab from JRS), are dissolved in 1157.9g of isopropanol at 78° C. The solution is sprayed entirely on 300.0 gof IR particles prepared above in a fluid bed spray coater apparatusGlatt G.P.C.G.1.1 with inlet temperature 48° C., spraying rate around10.7 g per min and atomization pressure 1.3 bar. MR microparticles weredried for 2 hours with inlet temperature set to 56° C. Sodium oxybate MRcoated particles with mean diameter of 289 microns are obtained.

25.3 g of MR coated microparticles were mixed with 0.12 g of magnesiumstearate (from Peter Greven). The dissolution profile of 4000 mg of themixture which correspond to 2368 mg of sodium oxybate per vessel wasdetermined in 900 ml of 0.1N HCl and pH 6.8 phosphate buffer (0.05Mmonobasic potassium phosphate solution with pH adjusted to 6.8 with 5NNaOH) using the USP apparatus 2. Dissolution medium temperature wasmaintained at 37.0±0.5° C., and the rotating paddle speed was set at 75rpm. The release profiles are shown below in FIG. 45 and Tables 13a and13b.

TABLE 13a Dissolution data - 0.1N HCl Time (h) % dissolved 0 0 0.25 0 10 3 1 4 3 6 29 8 50 10 69 12 82 16 97 20 102

TABLE 13b Dissolution data - 50 mM pH 6.8 phosphate buffer Time (h) %dissolved 0 0 0.25 5 1 102 3 106

The qualitative composition of 4.5 g dose units comprising 50% of thedose as IR fraction and 50% of the dose as MR fraction is described inTable 13c.

TABLE 13c Quantity per Component Function 4.5 g dose (g) MRmicroparticles Modified release fraction 3.841 of sodium oxybate IRmicroparticles Immediate release 2.647 fraction of sodium oxybate Malicacid Acidifying agent 0.113 Xanthan gum Suspending agent 0.050Hydroxyethylcellulose Suspending agent 0.075 Carrageenan gum Suspendingagent 0.075 Magnesium stearate Lubricant 0.034 Total 6.835

After reconstitution with 50 ml of tap water and rinsing with 10 ml oftap water, the finished composition is expected to provide the followingdissolution profiles in FIGS. 46 and 47 and Tables 13d and 13e in 840 mlof 0.1N HCl and pH6.8 phosphate buffer (0.05M monobasic potassiumphosphate solution with pH adjusted to 6.8 with 5N NaOH) using a USPapparatus 2, at 37.0±0.5° C. and the rotating paddle speed at 75 rpm.

TABLE 13d Time (h) % dissolved in 0.1N HCl 0.0 0 0.3 50 1.0 50 3.0 504.0 52 6.0 64 8.0 75 10.0 84 12.0 91 16.0 98 20.0 101

TABLE 13e Time (h) % dissolved in pH 6.8 buffer 0 0 0.25 53 1.0 101 3103

Example 14. MR Particles with Larger Core Size (160 Microns)

Different prototypes were also developed to evaluate the impact of thecore size on the dissolution of the formulation.

IR particles were prepared as follows: 1615.0 g of sodium oxybate and85.0 g of water soluble polymer polyvinylpyrrolidone (Povidone—Plasdone™K30 from ISP) were solubilized in 1894.3 g of absolute ethyl alcohol and1262.9 g of water. The solution was entirely sprayed onto 300 g ofmicrocrystalline cellulose spheres (Cellets™ 100 from Pharmatrans)(D[4,3]=160 microns) in a fluid bed spray coater apparatus GPCG1.1.Sodium oxybate IR particles with mean diameter of 310 microns wereobtained.

MR coated particles were prepared as follows: 25.7 g of methacrylic acidcopolymer type C (Eudragit™ L100-55 from Evonik), 51.5 g of methacrylicacid copolymer type B (Eudragit™ S100 from Evonik), 115.7 g ofhydrogenated cottonseed oil (Lubritab™ from JRS), were dissolved in1735.7 g of isopropanol at 78° C. The solution was sprayed entirely on450.0 g of IR particles in a fluid bed spray coater apparatus Glatt™G.P.C.G.1.1 with inlet temperature 47° C., spraying rate around 9.6 gper min and atomization pressure 1.6 bar. MR particles were dried for 2hours with inlet temperature set to 56° C. Sodium oxybate MR coatedparticles with mean diameter of 370 microns were obtained.

49.3 g of sodium oxybate MR particles were mixed with 0.52 g ofmagnesium stearate (from Peter Greven) and 0.26 g of colloidal silicondioxide (Aerosil™ 200 from Evonik). The dissolution profile of 4000 mgof the mixture which correspond to 2250 mg of sodium oxybate per vesselwas determined using the USP apparatus 2 in 900 ml of 0.1N HCl mediumand pH 6.8 phosphate buffer (0.05M monobasic potassium phosphatesolution—pH adjusted to 6.8 with 5N NaOH). Dissolution mediumtemperature was maintained at 37.0±0.5° C., and the rotating paddlespeed was set at 100 rpm. The release profile in 0.1N HCl and pH 6.8phosphate buffer is shown below in FIG. 48 and Tables 14a and 14b.

TABLE 14a Dissolution data - 0.1N HCl Time (h) % dissolved 0 0 0.25 0 11 3 2 6 3 8 7 10 18 12 37 16 75

TABLE 14b Dissolution data - 50 mM pH 6.8 phosphate buffer Time (h) %dissolved 0 0 0.25 9 0.5 95 1 101 3 101

The qualitative composition of 4.5 g dose units comprising 50% of thedose as IR fraction and 50% of the dose as MR fraction is described inTable 14c.

TABLE 14c Quantity per Component Function 4.5 g dose (g) MRmicroparticles Modified release fraction 2.786 of sodium oxybate IRmicroparticles Immediate release 3.981 fraction of sodium oxybate Malicacid Acidifying agent 0.113 Xanthan gum Suspending agent 0.050Hydroxyethylcellulose Suspending agent 0.075 Carrageenan gum Suspendingagent 0.075 Magnesium stearate Lubricant 0.037 Total 7.115

After reconstitution with 50 ml of tap water and rinsing with 10 ml oftap water, the finished composition is expected to provide thedissolution profiles in FIGS. 49 and 50 and Table 14d and 14e in 840 mlof 0.1N HCl and in pH6.8 phosphate buffer (0.05M monobasic potassiumphosphate solution with pH adjusted to 6.8 with 5N NaOH) using a USPapparatus 2, at 37.0±0.5° C. and the rotating paddle speed at 75 rpm.

TABLE 14d Time (hour) % dissolved in 0.1N HCl 0 0 0.25 50 1 51 4 51 6 528 53 10 59 12 69 16 87

TABLE 14e Time (hour) % dissolved in pH 6.8 buffer 0 0 0.25 55 1 101 3101

Example 15. MR Microparticles with Different Ratios of Lubritab™ andEudragit™

Different prototypes were developed to evaluate the effect of the ratiobetween Lubritab™ and Eudragit™ on the formulation.

Example 15A: 30% Lubritab™; Cellets™ 127; Coating Level=35%

IR particles were prepared as follows: 1615.0 g of Sodium Oxybate and85.0 g of water soluble polymer polyvinylpyrrolidone (Povidone—Plasdone™K30 from ISP) were solubilized in 1894.3 g of absolute ethyl alcohol and1262.9 g of water. The solution was entirely sprayed onto 300 g ofmicrocrystalline cellulose spheres (Cellets™ 100 from Pharmatrans) in afluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particleswith mean diameter of 272 microns were obtained.

MR coated particles were prepared as follows: 50.2 g of Methacrylic acidcopolymer Type C (Eudragit™ L100-55 from Evonik), 100.6 g of Methacrylicacid copolymer Type B (Eudragit™ S100 from Evonik), 64.6 g ofHydrogenated cottonseed oil (Lubritab™ from JRS), were dissolved in1943.5 g of isopropanol at 78° C. The solution was sprayed entirely on400.0 g of IR particles in a fluid bed spray coater apparatus Glatt™G.P.C.G.1.1 with inlet temperature 48° C., spraying rate around 11.0 gper min and atomization pressure 1.3 bar. MR microparticles were driedfor 2 hours with inlet temperature set to 56° C. Sodium oxybate MRcoated particles with mean diameter of 403 microns were obtained.

17.9 g of sodium oxybate MR microparticles were mixed with 0.1 g ofmagnesium stearate (from Peter Greven). The dissolution profile of 4308mg of the mixture which corresponds to 2250 mg of sodium oxybate pervessel was determined using the USP apparatus 2 in 900 ml of 0.1N HClmedium. Dissolution medium temperature was maintained at 37.0±0.5° C.,and the rotating paddle speed was set at 75 rpm. The release profile isshown in FIG. 51 and Table 15a.

TABLE 15a Time (h) % dissolved in 0.1N HCl 0 0 0.25 3 1 5 3 69 4 96 6101 8 102 10 102

Alternative MR coated particles of sodium oxybate were preparedaccording to the above manufacturing protocol with the coating leveladjusted to 50% instead of 35%. The dissolution profile of thealternative sodium oxybate MR particles was determined using the sameprotocol as above. The 0.1N HCl dissolution profile is shown in FIG. 52and Table 15b.

TABLE 15b Time (h) % dissolved 0 0 0.25 1 1 1 3 36 4 67 6 95 8 98 10 98

The finished composition, which contains a 50:50 mixture of MR and IRsodium oxybate particles calculated on their sodium oxybate content, wasprepared as follows: 153.3 g of the above IR microparticles, 235.8 g ofthe above sodium oxybate MR microparticles with a coating level of 30%,6.2 g of malic acid (D/L malic acid regular from Bartek), 2.7 g ofxanthan gum (Xantural™ 75 from CP Kelco), 4.1 g of carrageenan gum(Viscarin™ PH109 from FMC Biopolymer), 4.1 g of hydroxyethylcellulose(Natrosol™ 250M from Ashland) and 2.0 g of magnesium stearate (fromPeter Greven) were mixed in a Roue-Roehn mixer. Individual doses of 7.42g (corresponding to a 4.5 g dose with half of the dose asimmediate-release fraction and half of the dose as modified releasefraction) were weighed.

FIG. 53 and Table 15c below depict dissolution profiles determined usinga USP apparatus 2 in 0.1N HCl. The dissolution medium was maintained at37.0±0.5° C. and the rotating paddle speed was fixed at 75 rpm. Singledose units were poured in a container containing 50 mL of tap water.After 5 minutes, the suspension was poured in the dissolution vesselcontaining 840 mL of 0.1N HCl dissolution medium. 10 mL of water wereused to rinse the container and were added to the dissolution vessel.

TABLE 15c Time (hour) % dissolved 0 0 0.25 45 1 52 2 92 3 94 4 97 6 97 897 10 96

Example 15B: Celphere™ CP203 as Neutral Cores and Coating Level=35%

IR particles were prepared as follows: 665.0 g of Sodium Oxybate and35.0 g of water soluble polymer polyvinylpyrrolidone (Povidone—Plasdone™K30 from ISP) were solubilized in 781.2 g of absolute ethyl alcohol and521.6 g of water. The solution was entirely sprayed onto 300 g ofmicrocrystalline cellulose spheres (Celphere™ CP203 from AsahiKasei—mean diameter D[4,3]=250 microns) in a fluid bed spray coaterapparatus GPCG1.1. Sodium oxybate IR particles with mean diameter of 398microns were obtained.

MR coated particles were prepared as follows: 37.6 g of Methacrylic acidcopolymer Type C (Eudragit™ L100-55 from Evonik), 75.4 g of Methacrylicacid copolymer Type B (Eudragit™ S100 from Evonik), 48.5 g ofHydrogenated cottonseed oil (Lubritab™ from JRS), were dissolved in1458.0 g of isopropanol at 78° C. The solution was sprayed entirely on300.0 g of IR particles in a fluid bed spray coater apparatus Glatt™G.P.C.G.1.1 with inlet temperature 48° C., spraying rate around 11.7 gper min and atomization pressure 1.6 bar. MR microparticles were driedfor 2 hours with inlet temperature set to 56° C. Sodium oxybate MRcoated particles with mean diameter of 491 microns were obtained.

17.0 g of MR microparticles were mixed with 0.08 g of magnesium stearate(from Peter Greven). The dissolution profile of 5210 mg of the mixturewhich corresponds to 2250 mg of sodium oxybate per vessel was determinedusing the USP apparatus 2 in 900 ml of 0.1N HCl medium and in pH 6.8phosphate buffer (0.05M monobasic potassium phosphate solution—pHadjusted to 6.8 with 5N NaOH). Dissolution medium temperature wasmaintained at 37.0±0.5° C., and the rotating paddle speed was set at 75rpm. The release profile is shown in FIG. 54 and Tables 15d and 15e.

TABLE 15d Dissolution data - 0.1N HCl Time (hour) % dissolved 0 0 0.25 31 3 3 45 4 77 6 96 8 98 10 98

TABLE 15e Dissolution data - 50 mM pH 6.8 phosphate buffer Time (h) %dissolved 0 0 0.25 1 0.5 22 0.75 87 1 98 2 97

The qualitative composition of 4.5 g dose units comprising 50% of thedose as IR fraction and 50% of the dose as MR fraction is described inTable 15f.

TABLE 15f Quantity per Component Function 4.5 g dose (g) MRmicroparticles Modified release fraction of 5.205 sodium oxybate IRmicroparticles Immediate release fraction of 3.383 sodium oxybate Malicacid Acidifying agent 0.113 Xanthan gum Suspending agent 0.050Hydroxyethylcellulo Suspending agent 0.075 Carrageenan gum Suspendingagent 0.075 Magnesium stearate Lubricant 0.045 Total 8.946

After reconstitution, the finished composition is expected to exhibitthe dissolution profiles in FIGS. 55 and 56 and Tables 15g and 15h in0.1N HCl and in pH6.8 phosphate buffer (0.05M monobasic potassiumphosphate solution with pH adjusted to 6.8 with 5N NaOH) using a USPapparatus 2, at 37.0±0.5° C. and the rotating paddle speed at 75 rpm.

TABLE 15g % dissolved in 0.1N Time (h) HCl 0 0 0.25 51 1 51 3 73 4 88 698 8 99 10 99

TABLE 15h % dissolved in pH 6.8 Time (h) buffer 0 0 0.25 50 0.5 61 0.7593 1 99 2 99

Example 15C: 40% Lubritab™ (Coating Level=40%)

IR pellets were prepared as follows: 1615.0 g of Sodium Oxybate and 85.0g of water soluble polymer polyvinylpyrrolidone (Povidone—Plasdone™ K30from ISP) were solubilized in 1903.2 g of absolute ethyl alcohol and1267.1 g of water. The solution was entirely sprayed onto 300 g ofmicrocrystalline cellulose spheres (Cellets™ 127 from Pharmatrans) in afluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particleswith mean diameter of 268 microns were obtained.

MR coated particles were prepared as follows: 40.6 g of Methacrylic acidcopolymer Type C (Eudragit™ L100-55 from Evonik), 80.1 g of Methacrylicacid copolymer Type B (Eudragit™ S100 from Evonik), 80.5 g ofHydrogenated cottonseed oil (Lubritab™ from JRS), were dissolved in1799.4 g of isopropanol at 78° C. The solution was sprayed entirely on300.0 g of IR particles in a fluid bed spray coater apparatus Glatt™G.P.C.G.1.1 with inlet temperature 48° C., spraying rate around 10.5 gper min and atomization pressure 1.3 bar. MR microparticles were driedfor 2 hours with inlet temperature set to 56° C. Sodium oxybate MRcoated particles with mean diameter of 348 microns were obtained.

20.0 g of MR coated particles were mixed with 0.1 g of magnesiumstearate (from Peter Greven). The dissolution profile of 4700 mg of themixture which corresponds to 2250 mg of sodium oxybate per vessel wasdetermined using the USP apparatus 2 in 900 ml of 0.1N HCl medium.Dissolution medium temperature was maintained at 37.0±0.5° C., and therotating paddle speed was set at 75 rpm. The release profile is shown inFIG. 57 and Table 15i.

TABLE 15i Time (h) % dissolved in 0.1N HCl 0 0 0.25 0 1 0 3 1 4 8 6 52 884 10 95 12 97 16 98

The finished composition, which contains a 50:50 mixture of MR and IRparticles calculated on their sodium oxybate content, was prepared asfollows: 156.0 g of the above IR particles, 260.0 g of the above MRcoated particles, 6.3 g of malic acid (D/L malic acid regular fromBartek), 2.8 g of xanthan gum (Xantural™ 75 from CP Kelco), 4.2 g ofcarrageenan gum (Viscarin™ PH209 from FMC Biopolymer), 4.2 g ofhydroxyethylcellulose (Natrosol™ 250M from Ashland) and 2.2 g ofmagnesium stearate (from Peter Greven) were mixed in a Roue-Roehn mixer.Individual doses of 7.78 g (corresponding to a 4.5 g dose with half ofthe dose as immediate-release fraction and half of the dose as modifiedrelease fraction) were weighed.

FIGS. 58 and 59 and Tables 15j and 15k below depict dissolution profilesdetermined in 0.1N HCl and pH 6.8 buffer (0.05M monobasic potassiumphosphate solution with pH adjusted to 6.8 with 5N NaOH) using a USPapparatus 2. The dissolution medium was maintained at 37.0±0.5° C. andthe rotating paddle speed was fixed at 75 rpm. Single dose units werepoured in a container containing 50 mL of tap water. After 5 minutes,the suspension was poured in the dissolution vessel containing 840 mL of0.1N HCl dissolution medium. 10 mL of water were used to rinse thecontainer and were added to the dissolution vessel.

TABLE 15j Time (h) % dissolved in 0.1N HCl 0 0 0.25 48 1 52 3 52 4 62 689 8 96 10 97 12 98 16 98 20 97

TABLE 15k Time (h) % dissolved in pH 6.8 buffer 0 0 0.25 49 0.5 85 1 912 96 3 104

Example 15D: 70% Lubritab™ (Coating Level 25%)

IR particles were prepared as follows: 1615.1 g of Sodium Oxybate and85.0 g of water soluble polymer polyvinylpyrrolidone (Povidone—Plasdone™K30 from ISP) were solubilized in 1894.4 g of absolute ethyl alcohol and1262.9 g of water. The solution was entirely sprayed onto 300 g ofmicrocrystalline cellulose spheres (Cellets™ 127 from Pharmatrans) in afluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particleswith mean diameter of 272 microns were obtained.

MR coated particles were prepared as follows: 13.3 g of Methacrylic acidcopolymer Type C (Eudragit™ L100-55 from Evonik), 26.8 g of Methacrylicacid copolymer Type B (Eudragit™ S100 from Evonik), 93.3 g ofHydrogenated cottonseed oil (Lubritab™ from JRS), were dissolved in1200.3 g of isopropanol at 78° C. The solution was sprayed entirely on400.0 g of IR particles in a fluid bed spray coater apparatus Glatt™G.P.C.G.1.1 with inlet temperature 48° C., spraying rate around 10.6 gper min and atomization pressure 1.3 bar. MR microparticles were driedfor 2 hours with inlet temperature set to 56° C. Sodium oxybate MRcoated particles with mean diameter of 313 microns were obtained.

17.0 g of MR coated particles were mixed with 0.06 g of magnesiumstearate (from Peter Greven). The dissolution profile of 3750 mg of themixture which corresponds to 2250 mg of sodium oxybate per vessel wasdetermined using the USP apparatus 2 in 900 ml of 0.1N HCl medium andpH6.8 phosphate buffer (0.05M monobasic potassium phosphate solution—pHadjusted to 6.8 with 5N NaOH). Dissolution medium temperature wasmaintained at 37.0±0.5° C., and the rotating paddle speed was set at 75rpm. The release profile is shown in FIG. 60 and Tables 15l and 15m.

TABLE 15l Dissolution profile in 0.1N HCl Time (h) % dissolved 0 0.00.25 5 1 4 3 5 4 5 6 8 8 33 10 78 12 98 16 103

TABLE 15M Dissolution profile in 50 mM pH 6.8 phosphate buffer Time (h)% dissolved 0 0.0 0.25 1 0.5 45 1 97 2 108 3 114

The finished composition, which contains a 50:50 mixture of MR and IRparticles calculated on their sodium oxybate content, was prepared asfollows: 153.3 g of the above IR particles, 204.3 g of the above MRcoated particles, 6.2 g of Malic acid (D/L malic acid regular fromBartek), 2.7 g of xanthan gum (Xantural™ 75 from CP Kelco), 4.1 g ofcarrageenan gum (Viscarin™ PH209 from FMC Biopolymer), 4.1 g ofhydroxyethylcellulose (Natrosol™ 250M from Ashland) and 1.9 g ofmagnesium stearate (from Peter Greven) were mixed in a Roue-Roehn mixer.Individual doses of 6.85 g (corresponding to a 4.5 g dose with half ofthe dose as immediate-release fraction and half of the dose as modifiedrelease fraction) were weighed.

FIG. 61 and Table 15n depict the dissolution profiles determined in 0.1NHCl using a USP apparatus 2. The dissolution medium was maintained at37.0±0.5° C. and the rotating paddle speed was fixed at 75 rpm. Singledose units were poured in a container containing 50 mL of tap water.After 5 minutes, the suspension was poured in the dissolution vesselcontaining 840 mL of 0.1N HCl dissolution medium. 10 mL of water wereused to rinse the container and were added to the dissolution vessel.

TABLE 15n Time (h) % dissolved 0 0 0.25 48 1 52 3 52 4 52 6 55 8 76 1095 12 100 16 100 20 100

Based on the dissolution profile of the MR coated particles in pH 6.8phosphate buffer, single dose units are expected to have the dissolutionprofile in pH6.8 buffer shown in FIG. 62 and in Table 15o.

TABLE 15o Time (h) % dissolved in pH 6.8 buffer 0 0.0 0.25 51 0.5 72 199 2 104 3 107

Example 16. Evaluation of Different Hydrophobic Compounds in the Coating

Prototypes with different hydrophobic coatings were prepared andevaluated to determine the effect of coating type on the dissolution ofthe formulations.

Example 16A: Glyceryl Dibehenate (Compritol™ ATO888)

IR particles were prepared as follows: 1615.0 g of Sodium Oxybate and85.0 g of water soluble polymer polyvinylpyrrolidone (Povidone—Plasdone™K30 from ISP) were solubilized in 1903.2 g of absolute ethyl alcohol and1267.1 g of water. The solution was entirely sprayed onto 300 g ofmicrocrystalline cellulose spheres (Cellets™ 127 from Pharmatrans) in afluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particleswith mean diameter of 268 microns were obtained.

MR coated particles were prepared as follows: 22.9 g of Methacrylic acidcopolymer Type C (Eudragit™ L100-55 from Evonik), 45.8 g of Methacrylicacid copolymer Type B (Eudragit™ S100 from Evonik), 102.9 g of glyceryldibehenate (Compritol™ ATO 888 from Gattefossé), were dissolved in1371.8 g of isopropanol at 78° C. The solution was sprayed entirely on400.0 g of IR particles in a fluid bed spray coater apparatus Glatt™G.P.C.G.1.1 with inlet temperature 48° C., spraying rate around 11.7 gper min and atomization pressure 1.6 bar. MR microparticles were driedfor 2 hours with inlet temperature set to 56° C. Sodium oxybate MRcoated particles with mean diameter of 322 microns were obtained.

17.0 g of MR coated particles were mixed with 0.1 g of magnesiumstearate (from Peter Greven). The dissolution profile of 4000 mg of themixture which corresponds to 2250 mg of sodium oxybate per vessel wasdetermined using the USP apparatus 2 in 900 ml of 0.1N HCl medium and inpH 6.8 phosphate buffer (0.05M monobasic potassium phosphate solution—pHadjusted to 6.8 with 5N NaOH). Dissolution medium temperature wasmaintained at 37.0±0.5° C., and the rotating paddle speed was set at 75rpm. The release profile is shown in FIG. 63 and Tables 16a and 16b.

TABLE 16a Dissolution profile - 0.1N HCl Time (h) % dissolved 0 0 0.25 01 1 3 3 4 6 6 31 8 67 10 90 12 98 16 100

TABLE 16b Dissolution profile - 50 mM pH 6.8 phosphate buffer Time (h) %dissolved 0 0 0.25 1 1 102 3 105

The finished composition, which contains a 50:50 mixture of MR and IRparticles calculated on their sodium oxybate content, was prepared asfollows: 181.1 g of the above IR particles, 258.7 g of the above MRcoated particles, 7.3 g of Malic acid (D/L malic acid regular fromBartek), 3.3 g of xanthan gum (Xantural™ 75 from CP Kelco), 4.9 g ofcarrageenan gum (Viscarin™ PH209 from FMC Biopolymer), 4.9 g ofhydroxyethylcellulose (Natrosol™ 250M from Ashland) and 2.3 g ofmagnesium stearate (from Peter Greven) were mixed in a Roue-Roehn mixer.Individual doses of 7.12 g (corresponding to a 4.5 g dose with half ofthe dose as immediate-release fraction and half of the dose as modifiedrelease fraction) were weighed.

FIG. 64 and Table 16c depict dissolution profiles determined in 0.1N HClusing a USP apparatus 2. The dissolution medium was maintained at37.0±0.5° C. and the rotating paddle speed was fixed at 75 rpm. Singledose units were poured in a container containing 50 mL of tap water.After 5 minutes, the suspension was poured in the dissolution vesselcontaining 840 mL of 0.1N HCl dissolution medium. 10 mL of water wereused to rinse the container and were added to the dissolution vessel.

TABLE 16c Time (hour) % dissolved in 0.1N HCl 0 0 0.25 46 1 50 3 51 4 566 78 8 92 10 96 12 97 16 96

Based on the dissolution profile of the MR microparticles alone in pH6.8 phosphate buffer, single dose units are expected to have thedissolution profile at pH6.8 shown in FIG. 65 and in Table 16d.

TABLE 16d Time (hour) % dissolved in pH 6.8 buffer 0 0 0.25 50 1 101 3102

Example 16B: 60% Candelilla Wax with Coating Level of 20%

IR particles were prepared as follows: 1615.1 g of Sodium Oxybate and85.0 g of water soluble polymer polyvinylpyrrolidone (Povidone—Plasdone™K30 from ISP) were solubilized in 1894.4 g of absolute ethyl alcohol and1262.9 g of water. The solution was entirely sprayed onto 300 g ofmicrocrystalline cellulose spheres (Cellets™ 127 from Pharmatrans) in afluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particleswith mean diameter of 255 microns were obtained.

MR coated particles were prepared as follows: 13.3 g of Methacrylic acidcopolymer Type C (Eudragit™ L100-55 from Evonik), 26.7 g of Methacrylicacid copolymer Type B (Eudragit™ S100 from Evonik), 60.0 g of candelillawax (Kahlwax™ 2039 L from Brenntag), were dissolved in 902.2 g ofisopropanol at 78° C. The solution was sprayed entirely on 400.0 g of IRparticles in a fluid bed spray coater apparatus Glatt™ G.P.C.G.1.1 withinlet temperature 48° C., spraying rate around 12.8 g per min andatomization pressure 1.3 bar. MR microparticles were dried for 2 hourswith inlet temperature set to 56° C. Sodium oxybate MR coated particleswith mean diameter of 289 microns were obtained.

21.2 g of MR microparticles were mixed with 0.11 g of magnesium stearate(from Peter Greven). The dissolution profile of 4000 mg of the mixturewhich corresponds to 2570 mg of sodium oxybate per vessel was determinedusing the USP apparatus 2 in 900 ml of 0.1N HCl medium and in pH 6.8phosphate buffer (0.05M monobasic potassium phosphate solution—pHadjusted to 6.8 with 5N NaOH). Dissolution medium temperature wasmaintained at 37.0±0.5° C., and the rotating paddle speed was set at 75rpm. The release profiles are shown below in FIG. 66 and Tables 16e and16f.

TABLE 16e Dissolution profile - 0.1N HCl Time (h) % dissolved 0 0 0.25 01 0 3 0 4 1 6 2 8 2 10 2 12 2 16 3 20 4

TABLE 16f Dissolution profile - 50 mM pH 6.8 phosphate buffer Time (h) %dissolved 0 0 0.25 0 0.5 10 0.75 62 1 89 2 101

The qualitative composition of 4.5 g dose units comprising 50% of thedose as IR fraction and 50% of the dose as MR fraction is described inTable 16 g.

TABLE 16g Quantity per Component Function 4.5 g dose (g) MRmicroparticles Modified release fraction 3.483 of sodium oxybate IRmicroparticles Immediate release 2.786 fraction of sodium oxybate Malicacid Acidifying agent 0.113 Xanthan gum Suspending agent 0.050Hydroxyethylcellulose Suspending agent 0.075 Carrageenan gum Suspendingagent 0.075 Magnesium stearate Lubricant 0.033 Total 6.615

The finished composition, which contains a 50:50 mixture of MR and IRparticles calculated on their sodium oxybate content, can be prepared asfollows: 200.0 g of the above IR particles, 250.0 g of the above MRcoated particles, 8.1 g of Malic acid (D/L malic acid regular fromBartek), 3.6 g of xanthan gum (Xantural™ 75 from CP Kelco), 5.4 g ofcarrageenan gum (Viscarin™ PH209 from FMC Biopolymer), 5.4 g ofhydroxyethylcellulose (Natrosol™ 250M from Ashland) and 2.4 g ofmagnesium stearate (from Peter Greven) were mixed in a Roue-Roehn mixer.Individual doses of 6.61 g (corresponding to a 4.5 g dose with half ofthe dose as immediate-release fraction and half of the dose as modifiedrelease fraction) were weighed.

After reconstitution, the finished composition is expected to providethe dissolution profiles in FIGS. 67 and 68 and Tables 16h and 16i in0.1N HCl and in pH6.8 phosphate buffer (0.05M monobasic potassiumphosphate solution with pH adjusted to 6.8 with 5N NaOH) using a USPapparatus 2, at 37.0±0.5° C. and the rotating paddle speed at 75 rpm.

TABLE 16h Time (hour) % dissolved in 0.1N HCl 0 0 0.25 50 1 50 3 50 4 506 51 8 51 10 51 12 51 16 52 20 52

TABLE 16i Time (hour) % dissolved in pH 6.8 buffer 0 0 0.25 50 0.5 550.75 81 1 94 2 100

Example 16C: 40% Candelilla Wax (Coating Level=20%)

IR particles were prepared as follows: 1615.1 g of Sodium Oxybate and85.0 g of water soluble polymer polyvinylpyrrolidone (Povidone—Plasdone™K30 from ISP) were solubilized in 1894.4 g of absolute ethyl alcohol and1262.9 g of water. The solution was entirely sprayed onto 300 g ofmicrocrystalline cellulose spheres (Cellets™ 127 from Pharmatrans) in afluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particleswith mean diameter of 270 microns were obtained.

MR coated particles were prepared as follows: 20.0 g of Methacrylic acidcopolymer Type C (Eudragit™ L100-55 from Evonik), 40.0 g of Methacrylicacid copolymer Type B (Eudragit™ S100 from Evonik), 40.0 g of candelillawax (Kahlwax™ 2039 L from Brenntag), were dissolved in 904.0 g ofisopropanol at 78° C. The solution was sprayed entirely on 400.0 g of IRparticles in a fluid bed spray coater apparatus Glatt™ G.P.C.G.1.1 withinlet temperature 48° C., spraying rate around 10.9 g per min andatomization pressure 1.3 bar. MR microparticles were dried for 2 hourswith inlet temperature set to 56° C. Sodium oxybate MR coated particleswith mean diameter of 302 microns were obtained.

17.0 g of MR microparticles were mixed with 0.08 g of magnesium stearate(from Peter Greven). The dissolution profile of 3500 mg of the mixturewhich corresponds to 2250 mg of sodium oxybate per vessel was determinedusing the USP apparatus 2 in 900 ml of 0.1N HCl medium and pH 6.8phosphate buffer (0.05M monobasic potassium phosphate solution—pHadjusted to 6.8 with 5N NaOH) is given in FIG. 69 and Tables 16j and16k. Dissolution medium temperature was maintained at 37.0±0.5° C., andthe rotating paddle speed was set at 75 rpm.

TABLE 16j Dissolution profile in 0.1N HCl Time (h) % dissolved 0 0 0.250 1 3 3 6 4 8 6 9 8 15 10 37 12 70 16 97 20 100

TABLE 16k Dissolution profile in 50 mM pH 6.8 phosphate buffer Time (h)% dissolved 0 0 0.25 24 0.5 86 0.75 99 1 100 2 100

The qualitative composition of 4.5 g dose units comprising 50% of thedose as IR fraction and 50% of the dose as MR fraction is described inTable 16l.

TABLE 16l Quantity per Component Function 4.5 g dose (g) MRmicroparticles Modified release fraction 3.483 of sodium oxybate IRmicroparticles Immediate release 2.786 fraction of sodium oxybate Malicacid Acidifying agent 0.113 Xanthan gum Suspending agent 0.050Hydroxyethylcellulose Suspending agent 0.075 Carrageenan gum Suspendingagent 0.075 Magnesium stearate Lubricant 0.033 Total 6.615

The finished composition, which contains a 50:50 mixture of MR and IRparticles calculated on their sodium oxybate content, was prepared asfollows: 122.7 g of the above IR particles, 153.2 g of the above MRcoated particles, 5.0 g of malic acid (D/L malic acid regular fromBartek), 2.2 g of xanthan gum (Xantural™ 75 from CP Kelco), 3.3 g ofcarrageenan gum (Viscarin™ PH209 from FMC Biopolymer), 3.3 g ofhydroxyethylcellulose (Natrosol™ 250M from Ashland) and 1.5 g ofmagnesium stearate (from Peter Greven) were mixed in a Roue-Roehn mixer.Individual doses of 6.62 g (corresponding to a 4.5 g dose with half ofthe dose as immediate-release fraction and half of the dose as modifiedrelease fraction) were weighed.

FIG. 70 and Table 16m depict dissolution profiles determined using a USPapparatus 2 in 0.1N HCl. The dissolution medium was maintained at37.0±0.5° C. and the rotating paddle speed was fixed at 75 rpm. Singledose units were poured in a container containing 50 mL of tap water.After 5 minutes, the suspension was poured in the dissolution vesselcontaining 840 mL of 0.1N HCl dissolution medium. 10 mL of water wereused to rinse the container and were added to the dissolution vessel.

TABLE 16m Time (hour) % dissolved in 0.1N HCl 0 0 0.25 47 1 51 3 51 4 526 52 8 55 10 72 12 89 16 97

Based on the dissolution profile of the MR coated particles in pH6.8phosphate buffer, 4.5 g single dose units of the finished compositionsare expected to provide the dissolution profile in pH 6.8 phosphatebuffer shown in FIG. 71 and in Table 16n.

TABLE 16n Time (h) % dissolved in pH 6.8 buffer 0 0 0.25 62 0.5 93 0.7599 1 100 2 100

Example 16D—60% Cetyl Alcohol (Kolliwax™ CA)

IR particles were prepared as follows: 1615.1 g of Sodium Oxybate and85.0 g of water soluble polymer polyvinylpyrrolidone (Povidone—Plasdone™K30 from ISP) were solubilized in 1898.7 g of absolute ethyl alcohol and1262.9 g of water. The solution was entirely sprayed onto 300 g ofmicrocrystalline cellulose spheres (Cellets™ 127 from Pharmatrans) in afluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particleswith mean diameter of 272 microns were obtained.

MR coated particles were prepared as follows: 22.8 g of methacrylic acidcopolymer Type C (Eudragit™ L100-55 from Evonik), 45.8 g of Methacrylicacid copolymer Type B (Eudragit™ S100 from Evonik), 102.9 g of cetylalcohol (Kolliwax™ CA from BASF), were dissolved in 1472.5 g ofisopropanol and 77.7 g of water at room temperature. The solution wassprayed entirely on 400.0 g of IR particles in a fluid bed spray coaterapparatus Glatt™ G.P.C.G.1.1 with inlet temperature 48° C., sprayingrate around 14.5 g per min and atomization pressure 2.5 bar. Sodiumoxybate MR coated particles with mean diameter of 315 microns wereobtained.

16.4 g of MR microparticles were mixed with 0.08 g of magnesium stearate(from Peter Greven). The dissolution profile of 4000 mg of the mixturewhich corresponds to 2250 mg of sodium oxybate per vessel was determinedusing the USP apparatus 2 in 900 ml of 0.1N HCl medium is given in FIG.72 and Table 16o. Dissolution medium temperature was maintained at37.0±0.5° C., and the rotating paddle speed was set at 75 rpm.

TABLE 16o Time (h) % dissolved in 0.1N HCl 0 0 0.25 13 1 84 3 103 4 1036 103 8 103 10 104 12 104 16 103 20 102

Example 17. Effect of Eudragit™ Selection in the Coating of the MrMicroparticles

Further prototypes were developed and evaluate to determine the effectof the Eudragit™ selected on the dissolution of the MR microparticles.

Example 17A 100% Eudragit™ 5100

IR particles were prepared as follows: 1615.0 g of Sodium Oxybate and85.0 g of water soluble polymer polyvinylpyrrolidone (Povidone—Plasdone™K30 from ISP) were solubilized in 1894.3 g of absolute ethyl alcohol and1262.9 g of water. The solution was entirely sprayed onto 300 g ofmicrocrystalline cellulose spheres (Cellets™ 127 from Pharmatrans) in afluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particleswith mean diameter of 285 microns were obtained.

Sodium oxybate IR seal-coated particles were prepared by coating the IRparticles described above with a seal-coat layer: 170.0 g ofhydroxypropylcellulose (Klucel™ EF Pharm from Hercules) were solubilizedin 4080.0 g of acetone. The solution was entirely sprayed onto 1530.0 gof the above IR particles in a fluid bed spray coater apparatus. Sodiumoxybate IR particles with volume mean diameter of about 298 microns wereobtained.

MR coated particles were prepared as follows: 100.0 g of Methacrylicacid copolymer Type B (Eudragit™ S100 from Evonik), 150.0 g ofHydrogenated cottonseed oil (Lubritab™ from JRS), were dissolved in2250.0 g of isopropanol at 78° C. The solution was sprayed entirely on750.0 g of the above IR particles in a fluid bed spray coater apparatusGlatt™ G.P.C.G.1.1 with inlet temperature 48° C., spraying rate around12.0 g per min and atomization pressure 1.6 bar. MR microparticles weredried for 2 hours with inlet temperature set to 56° C. Sodium oxybate MRcoated particles with mean diameter of 307 microns were obtained.

The dissolution profile of 2100 mg of the mixture which corresponds to1253 mg of sodium oxybate per vessel was determined using the USPapparatus 2 in 500 ml of 0.1N HCl medium is reported in FIG. 73 andTable 17a. Dissolution medium temperature was maintained at 37.0±0.5°C., and the rotating paddle speed was set at 100 rpm.

TABLE 17a Time (h) % dissolved 0 0 0.25 0 1 1 3 3 4 4 6 9 8 30 10 60 1281 16 92

The finished composition, which contains a 50:50 mixture of MR and IRparticles calculated on their sodium oxybate content, was prepared asfollows: 425.0 g of the above IR seal-coated particles, 510.0 g of theabove MR coated particles, 30.9 g of malic acid (D/L malic acid regularfrom Bartek), 4.9 g of xanthan gum (Xantural™ 180 from CP Kelco), 4.9 gof Aerosil™ 200 (amorphous anhydrous colloidal silicon dioxide fromEvonik) and 9.9 g of magnesium stearate (from Peter Greven) were mixedin a Roue-Roehn mixer. Individual doses of 7.18 g (corresponding to a4.5 g dose with half of the dose as immediate-release fraction and halfof the dose as modified release fraction) were weighed.

FIG. 74 and Table 17b below depict dissolution profiles determined usinga USP apparatus 2 in 0.1N HCl. The dissolution medium was maintained at37.0±0.5° C. and the rotating paddle speed was fixed at 100 rpm. Singledose units were poured in a container containing 50 mL of tap water.After 5 minutes, the suspension was poured in the dissolution vesselcontaining 840 mL of 0.1N HCl dissolution medium. 10 mL of water wereused to rinse the container and were added to the dissolution vessel.

TABLE 17b Time (hour) % dissolved in 0.1N HCl 0 0 0.25 50 1 50 3 50 4 516 55 8 67 10 84 12 91 16 94

FIG. 75 and Table 17c depict the dissolution profile determined using aUSP apparatus 2 in phosphate buffer pH 6.8 (0.05M monobasic potassiumphosphate solution—pH adjusted to 6.8 with 5N NaOH). The dissolutionmedium was maintained at 37.0±0.5° C. and the rotating paddle speed wasfixed at 100 rpm. Single dose units were poured in a containercontaining 50 mL of tap water. After 5 minutes, the suspension waspoured in the dissolution vessel containing 840 mL of pH 6.8 dissolutionmedium. 10 mL of water were used to rinse the container and were addedto the dissolution vessel.

TABLE 17c Time (hour) % dissolved 0 0 0.25 50 1 51 3 54 4 56 6 93 8 9910 100 12 100 16 97

Example 17B 100% Eudragit™ L100-55

IR particles were prepared as follows: 1615.0 g of Sodium Oxybate and85.1 g of water soluble polymer polyvinylpyrrolidone (Povidone—Plasdone™K30 from ISP) were solubilized in 1896.2 g of absolute ethyl alcohol and1264.4 g of water. The solution was entirely sprayed onto 300 g ofmicrocrystalline cellulose spheres (Cellets™ 127 from Pharmatrans) in afluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particleswith mean diameter of 275 microns were obtained.

MR coated particles were prepared as follows: 68.7 g of Methacrylic acidcopolymer Type C (Eudragit™ L100-55 from Evonik), 102.9 g ofhydrogenated cottonseed oil (Lubritab™ from JRS), were dissolved in1543.2 g of isopropanol at 78° C. The solution was sprayed entirely on400.0 g of IR particles in a fluid bed spray coater apparatus Glatt™G.P.C.G.1.1 with inlet temperature 46° C., spraying rate around 12.7 gper min and atomization pressure 1.3 bar. MR microparticles were driedfor 2 hours with inlet temperature set to 56° C. Sodium oxybate MRcoated particles with mean diameter of 328 microns were obtained.

17.0 g of MR microparticles were mixed with 0.09 g of magnesium stearate(from Peter Greven). The dissolution profile in of 4000 mg of themixture which corresponds to 2250 mg of sodium oxybate per vessel wasdetermined using the USP apparatus 2 in 900 ml of 0.1N HCl medium and inpH 6.8 phosphate buffer (0.05M monobasic potassium phosphate solution—pHadjusted to 6.8 with 5N NaOH) is given in FIG. 76 and Tables 17d and17e. Dissolution medium temperature was maintained at 37.0±0.5° C., andthe rotating paddle speed was set at 100 rpm.

TABLE 17d Dissolution profile in 0.1N HCl Time (h) % dissolved 0 0 0.250 1 2 3 3 4 6 6 53 8 95 10 99 12 99 16 99 20 99

TABLE 17e Dissolution profile in 50 mM pH 6.8 phosphate buffer Time (h)% dissolved 0 0 0.25 21 0.5 99 0.75 103 1 103 2 103

The finished composition, which contains a 50:50 mixture of MR and IRparticles calculated on their sodium oxybate content, was prepared asfollows: 153.3 g of the above IR particles, 219.0 g of the above MRcoated particles, 6.2 g of malic acid (D/L malic acid regular fromBartek), 2.8 g of xanthan gum (Xantural™ 75 from CP Kelco), 4.1 g ofcarrageenan gum (Viscarin™ PH209 from FMC Biopolymer), 4.1 g ofhydroxyethylcellulose (Natrosol™ 250M from Ashland) and 1.9 g ofmagnesium stearate (from Peter Greven) were mixed in a Roue-Roehn mixer.Individual doses of 7.12 g (corresponding to a 4.5 g dose with half ofthe dose as immediate-release fraction and half of the dose as modifiedrelease fraction) were weighed.

FIG. 77 and Table 17f depict dissolution profiles determined using a USPapparatus 2 in 0.1N HCl. The dissolution medium was maintained at37.0±0.5° C. and the rotating paddle speed was fixed at 75 rpm. Singledose units were poured in a container containing 50 mL of tap water.After 5 minutes, the suspension was poured in the dissolution vesselcontaining 840 mL of 0.1N HCl dissolution medium. 10 mL of water wereused to rinse the container and were added to the dissolution vessel.

TABLE 17f Time (hour) % dissolved 0 0 0.25 46 1 51 3 52 4 59 6 94 8 9810 98 12 98 16 98

Based on the dissolution profile of the MR coated particles in pH6.8phosphate buffer, 4.5 g single dose units of the finished compositionsare expected to provide the dissolution profile in pH 6.8 phosphatebuffer in FIG. 78 and Table 17g.

TABLE 17g Time (h) % dissolved in pH 6.8 buffer 0 0 0.25 61 0.5 99 0.75101 1 101 2 101

Example 17C Mixture Eudragit™ L100-S100 (50-50)

IR particles were prepared as follows: 1615.0 g of Sodium Oxybate and85.0 g of water soluble polymer polyvinylpyrrolidone (Povidone—Plasdone™K30 from ISP) were solubilized in 1903.2 g of absolute ethyl alcohol and1267.1 g of water. The solution was entirely sprayed onto 300 g ofmicrocrystalline cellulose spheres (Cellets™ 127 from Pharmatrans) in afluid bed spray coater apparatus GPCG1.1. Sodium oxybate IR particleswith mean diameter of 268 microns were obtained.

MR coated particles were prepared as follows: 34.3 g of Methacrylic acidcopolymer Type A (Eudragit™ L100 from Evonik), 34.3 g of Methacrylicacid copolymer Type B (Eudragit™ S100 from Evonik), 102.9 g ofHydrogenated cottonseed oil (Lubritab™ from JRS), were dissolved in1543.0 g of isopropanol at 78° C. The solution was sprayed entirely on400.0 g of IR particles in a fluid bed spray coater apparatus Glatt™G.P.C.G.1.1 with inlet temperature 48° C., spraying rate around 11.8 gper min and atomization pressure 1.3 bar. MR microparticles were driedfor 2 hours with inlet temperature set to 56° C. Sodium oxybate MRcoated particles with mean diameter of 316 microns were obtained.

24.0 g of MR microparticles were mixed with 0.12 g of magnesium stearate(from Peter Greven). The dissolution profile of 4050 mg of the mixturewhich corresponds to 2280 mg of sodium oxybate per vessel was determinedusing the USP apparatus 2 in 900 ml of 0.1N HCl medium and in pH 6.8phosphate buffer (0.05M monobasic potassium phosphate solution—pHadjusted to 6.8 with 5N NaOH) is given in FIG. 79 and Tables 17h and17i. Dissolution medium temperature was maintained at 37.0±0.5° C., andthe rotating paddle speed was set at 100 rpm.

TABLE 17h Dissolution profile in 0.1N HCl Time (h) % dissolved 0 0 0.250 1 2 3 2 4 3 6 7 8 31 10 62 12 83 16 98 20 100

TABLE 17i Dissolution profile in 50 mM pH 6.8 phosphate buffer Time (h)% dissolved 0 0 0.25 2 0.5 5 0.75 13 1 47 2 101

The finished composition, which contains a 50:50 mixture of MR and IRparticles calculated on their sodium oxybate content, was prepared asfollows: 223.0 g of the above IR particles, 318.4 g of the above MRcoated particles, 11.2 g of malic acid (D/L malic acid regular fromBartek), 4.0 g of xanthan gum (Xantural™ 75 from CP Kelco), 6.0 g ofcarrageenan gum (Viscarin™ PH209 from FMC Biopolymer), 6.0 g ofhydroxyethylcellulose (Natrosol™ 250M from Ashland) and 2.9 g ofmagnesium stearate (from Peter Greven) were mixed in a Roue-Roehn mixer.Individual doses of 7.14 g (corresponding to a 4.5 g dose with half ofthe dose as immediate-release fraction and half of the dose as modifiedrelease fraction) were weighed.

FIG. 80 and Table 17j depict dissolution profiles determined using a USPapparatus 2 in 0.1N HCl. The dissolution medium was maintained at37.0±0.5° C. and the rotating paddle speed was fixed at 75 rpm. Singledose units were poured in a container containing 50 mL of tap water.After 5 minutes, the suspension was poured in the dissolution vesselcontaining 840 mL of 0.1N HCl dissolution medium. 10 mL of water wereused to rinse the container and were added to the dissolution vessel.

TABLE 17j Time (hour) % dissolved 0 0 0.25 47 1 51 3 51 6 59 8 80 10 9212 96 16 97

Based on the dissolution profile of the MR coated particles in pH6.8phosphate buffer, 4.5 g single dose units of the finished compositionare expected to have the dissolution profile in pH 6.8 phosphate buffergiven in FIG. 81 and Table 17k.

TABLE 17k Time (h) % dissolved in pH 6.8 buffer 0 0 0.25 51 0.5 53 0.7556 1 73 2 100

Example 18: In Vivo Pharmacokinetic Study of Finished CompositionAccording to Example 1 (Dose Escalating Study)

Pharmacokinetic testing was undertaken in vivo in healthy humanvolunteers. Pharmacokinetic parameters were normalized by the dose. Toassess the dose-proportionality, log-transformed dose-normalized PKparameters were pairwise compared according to the statisticalmethodology described in FDA's 2013 Draft Guidance entitledBIOEQUIVALENCE STUDIES WITH PHARMACOKINETIC ENDPOINTS FOR DRUGSSUBMITTED UNDER AN ANDA (2013). All testing was performed in subjectstwo hours after eating a standardized dinner. A test product withfinished composition of Example 1 and manufactured at larger scale wasadministered in sequential ascending doses, 4.5 g, 7.5 g and 9 g, oneweek apart. The tested samples were manufactured as described in Table1c for 4.5 g and quantities were homothetically adjusted for the otherstrengths. The dissolution profiles of the MR portions of the testproduct are presented in FIGS. 86 and 87. The dissolution profiles ofthe test product are presented in FIGS. 88 and 89. The individualconcentrations of gamma-hydroxybutyrate and derived PK parameters aresummarized below (Tables 18a and 18b) and in FIG. 90.

TABLE 18a Pharmacokinetic Parameters of 4.5 g, 7.5 g, and 9 g Finishedcomposition Mean C_(max) Mean AUC_(inf) Mean AUC_(8 h) Median T_(max)Mean C_(8 h) of test (μg/mL) (μg/mL * h) (μg/mL * h) (hour) (μg/mL)product (% CV) (% CV) (% CV) (min-max) (% CV) 4.5 g 42.9 (37) 191 (50)174 (55) 1.71 (0.333-4) 4.76 (105) 7.5 g 72.0 (32) 357 (48) 320 (46) 1.5 (0.333-7) 19.7 (101) 9.0 g 84.5 (34) 443 (46) 379 (41)  2 (0.5-4)25.5 (97) 

AUC and C_(max) values increased more than dose-proportionally withincreasing doses of gamma-hydroxybutyrate formulated as the testproduct.

TABLE 18b Mean plasma concentration of gamma-hydroxybutyrate(microgram/mL) versus time of finished composition of test product Testproduct 4.5 g Test product 7.5 g Test product 9 g (2 h after meal) (2 hafter meal) (2 h after meal) Time (hr) (N = 20) (N = 20) (N = 12) 0 0.000.00 0.00 0.167 12.5 17.7 9.34 0.333 23.4 39.0 32.7 0.5 28.1 48.4 47.5 134.7 59.8 60.9 1.5 36.7 63.8 71.6 2 35.7 61.6 79.3 2.5 34.7 56.0 64.9 329.8 50.1 65.3 3.5 26.9 46.0 60.0 4 23.5 40.9 60.8 4.5 20.1 36.6 48.8 517.3 32.7 45.3 5.5 15.4 30.8 41.3 6 13.4 28.7 37.6 7 9.66 24.7 30.5 84.76 19.7 25.5 10 0.727 6.97 13.0 12 0.211 1.35 5.13 14 NC 0.392 0.820NC: Not Calculated

Table 18c compares the pharmacokinetic parameters AUC_(inf) and C_(8h)obtained for 4.5 g of the test product to the same parameters calculated2×2.25 g, i.e. 4.5 g total dose of Xyrem®.

TABLE 18c Comparison to 4.5 g divided dose of Xyrem ® Ratio (%)AUC_(inf) Mean Ratio (%) Mean composition to C_(8 h) C_(8 h) compositionAUC_(inf) AUC_(inf) (μg/mL) to C_(8 h) Xyrem ® (μg/mL * h) Xyrem ®Xyrem ® 9.24 NA 214 NA 2 × 2.25 g* Test product 4.76 52% 191 89% 4.5 g*data from the pilot PK study of example 3

Table 18d compares the pharmacokinetic parameters AUC_(inf) and C_(8h)obtained for 7.5 g of the test product to the same parameters calculated2×3.75 g, i.e. 7.5 g total dose of Xyrem®.

TABLE 18d Comparison to 7.5 g divided dose of Xyrem ® Ratio (%) Ratio(%) C_(8 h) AUC_(inf) Mean composition Mean composition to C_(8 h) toC_(8 h) AUC_(inf) AUC_(inf) (μg/mL) Xyrem ® (μg/mL * h) Xyrem ® Xyrem ®24.1 NA 432 NA 2 × 3.75 g (extrapolation from 2 × 4.5 g*) Test product19.7 82% 357 83% 7.5 g *based on data from NDA #21-196

Table 18e compares the pharmacokinetic parameters AUC_(inf) and C_(8h)obtained for 7.5 g and 9 g of the test product to the same parameterscalculated for 2×4.5 g, i.e. 9 g total dose of Xyrem®.

TABLE 18e Comparison to 9 g divided dose of Xyrem ® Ratio (%) AUC_(inf)Mean Ratio (%) Mean composition to C_(8 h) C_(8 h) composition AUC_(inf)AUC_(inf) (μg/mL) to C_(8 h) Xyrem ® (μg/mL * h) Xyrem ® Xyrem ® 28.9 NA518 NA 2 × 4.5 g* Test product 19.7 68% 357 69% 7.5 g Test product 25.588% 443 86% 9 g *data from NDA #21-196

For the finished composition administered at 4.5 g, mean C_(6h), meanC_(7h) are greater than, and mean C_(10h) are less than, the mean C_(4h)of the dose of Xyrem®. In addition, the ratio C_(3h)/C_(max) (Xyrem®) is1.03. The ratio C_(4h)/C_(max) (Xyrem®) is 0.81. The ratioC_(4.5h)/C_(max)(Xyrem®) is 0.69.

For the finished composition administered at 7.5 g, mean C_(6h), meanC_(7h) are greater than, and mean C_(10h) are less than, the mean C_(4h)of the dose of Xyrem®. In addition, the ratio C_(3h)/C_(max) (Xyrem®) is0.77. The ratio C_(4h)/C_(max) (Xyrem®) is 0.63. The ratioC_(4.5h)/C_(max) (Xyrem®) is 0.57.

For the finished composition administered at 9 g, mean C_(6h), meanC_(7h) are greater than, and mean C_(10h) are less than, the mean C_(4h)of the dose of Xyrem®. In addition, the ratio C_(3h)/C_(max) (Xyrem®) is0.84. The ratio C_(4h)/C_(max) (Xyrem®) is 0.78. The ratioC_(4.5h)/C_(max)(Xyrem®) is 0.63.

For the finished composition administered at 7.5 g compared to Xyrem® at2×4.5 g, i.e. total dose of 9 g, the ratio C_(3h)/C_(max)(Xyrem®) is0.65. The ratio C_(4h)/C_(max)(Xyrem®) is 0.53. The ratioC_(4.5h)/C_(max)(Xyrem®) is 0.47.

Throughout this application, various publications are referenced. Thedisclosures of these publications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this invention pertains. It willbe apparent to those skilled in the art that various modifications andvariations can be made in the present invention without departing fromthe scope or spirit of the invention. Other embodiments of the inventionwill be apparent to those skilled in the art from consideration of thespecification and practice of the invention disclosed herein. It isintended that the specification and examples be considered as exemplaryonly, with a true scope and spirit of the invention being indicated bythe following claims.

What is claimed is:
 1. A formulation of gamma-hydroxybutyratecomprising: an immediate release portion comprisinggamma-hydroxybutyrate; a modified release portion comprisinggamma-hydroxybutyrate; a suspending or viscosifying agent selected fromthe group consisting of xanthan gum, carrageenan gum, gellan gum, guargum, sodium alginate, calcium alginate, agar, sodium carboxymethylcellulose, microcrystalline cellulose, hydroxyethyl cellulose,hydroxypropylmethyl cellulose, and mixtures thereof; and an acidifyingagent selected from the group consisting of malic acid, citric acid,tartaric acid, adipic acid, boric acid, maleic acid, phosphoric acid,ascorbic acid, oleic acid, capric acid, caprylic acid, and benzoic acid;wherein the ratio of gamma-hydroxybutyrate in the immediate releaseportion and the modified release portion is from 10/90 to 65/35.
 2. Theformulation of claim 1, wherein the suspending or viscosifying agent ispresent at 1% to 15% by weight of the formulation, and the acidifyingagent is present at 1.2% to 15% by weight of the formulation.
 3. Themodified release formulation of claim 2, wherein: the suspending orviscosifying agent is a mixture of xanthan gum, carrageenan gum, andhydroxyethylcellulose, or a mixture of xanthan gum and carrageenan gum,and the acidifying agent is malic acid or tartaric acid.
 4. Theformulation of claim 1, wherein the formulation further comprises alubricant or glidant selected from the group consisting of magnesiumstearate, calcium stearate, zinc stearate, glyceryl monostearate,glyceryl palmitostearate, glycerol behenate, sodium stearyl fumarate,talc, or colloidal silicon dioxide.
 5. The formulation of claim 1,wherein the formulation is a dry particulate formulation or a powderedformulation.
 6. The formulation of claim 1, wherein the formulationcomprises 4.5 g, 6.0 g, 7.5 g, or 9.0 g of gamma-hydroxybutyrate.
 7. Theformulation of claim 1, wherein the formulation comprisesgamma-hydroxybutyrate in the form of sodium oxybate.
 8. The formulationof claim 1, wherein modified release portion comprises a hydrophobiccompound having a melting point equal to or greater than 40° C.
 9. Theformulation of claim 1, wherein a dose of the formulation achieves arelative bioavailability (RBA) of greater than 80% when compared to anequal dose of an immediate release liquid solution of sodium oxybateadministered at t₀ and t_(4h) in equally divided doses, whenadministered approximately two hours after a standardized evening meal.10. The formulation of claim 1, wherein a dose of the formulationachieves a ratio of mean AUC_(8h) to mean AUC_(inf) of greater than 0.80when administered once approximately two hours after a standardizedevening meal.
 11. The formulation of claim 1, wherein a dose of theformulation achieves a median T_(max) within 150 minutes of the medianT_(max) of half the dose of an immediate release liquid solution ofsodium oxybate, when administered approximately two hours after astandardized evening meal.
 12. The formulation of claim 1, wherein adose of the formulation achieves a mean C_(6h) or mean C_(7h) greaterthan, and a mean C_(10h) less than, the mean C_(4h) of half the dose ofan immediate release liquid solution of sodium oxybate, whenadministered approximately two hours after a standardized evening meal.13. The formulation of claim 1, wherein a dose of the formulationachieves a mean AUC_(inf) of greater than 80% of the mean AUC_(inf)provided by an equal dose of immediate release liquid solution of sodiumoxybate administered at t₀ and t_(4h) in equally divided dosesapproximately two hours after a standardized evening meal, and a meanC_(8h) less than 95% of the mean C_(8h) provided by an equal dose ofimmediate release liquid solution of sodium oxybate administered at t₀and t_(4h) in equally divided doses approximately two hours after astandardized evening meal.
 14. The formulation of claim 1, wherein theformulation releases at least 80% of its gamma-hydroxybutyrate at threehours when tested in a dissolution apparatus 2 according to USP 38 <711>in 900 mL of 0.05M monobasic potassium phosphate buffer pH 6.8 at atemperature of 37° C. and a paddle speed of 75 rpm.
 15. The formulationof claim 1, wherein the formulation releases from 10% to 65%, of itsgamma-hydroxybutyrate at one hour and three hours when tested in adissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1Nhydrochloric acid at a temperature of 37° C. and a paddle speed of 75rpm.
 16. The formulation of claim 1, wherein the modified releaseportion releases greater than 80% of its gamma-hydroxybutyrate at threehours when tested in a dissolution apparatus 2 according to USP 38 <711>in 900 mL of 0.05M monobasic potassium phosphate buffer pH 6.8 at atemperature of 37° C. and a paddle speed of 75 rpm.
 17. The formulationof claim 1, wherein the modified release portion releases less than 20%of its gamma-hydroxybutyrate at one hour when tested in a dissolutionapparatus 2 according to USP 38 <711> in 900 mL of 0.1N hydrochloricacid at a temperature of 37° C. and a paddle speed of 75 rpm.
 18. Theformulation of claim 1, wherein the modified release portion releasesgreater than 80% of its gamma-hydroxybutyrate at three hours in adissolution test started in 750 mL of 0.1N hydrochloric acid for 2 hoursthen switched to 950 mL 0.05M monobasic potassium phosphate bufferadjusted to pH 6.8 at a temperature of 37° C. and a paddle speed of 75rpm.
 19. The formulation of claim 1, wherein the immediate releaseportion releases greater than 80% of its gamma-hydroxybutyrate at onehour when tested in a dissolution apparatus 2 according to USP 38 <711>in 900 mL of 0.1N hydrochloric acid at a temperature of 37° C. and apaddle speed of 75 rpm.
 20. A formulation of gamma-hydroxybutyratecomprising: an immediate release portion comprisinggamma-hydroxybutyrate; a modified release portion comprisinggamma-hydroxybutyrate; from 1% to 15% of a suspending or viscosifyingagent; and from 1.2% to 15% of an acidifying agent; wherein the ratio ofgamma-hydroxybutyrate in the immediate release portion and the modifiedrelease portion is from 10/90 to 65/35; wherein the formulationcomprises an amount of gamma-hydroxybutyrate equivalent to from 3.0 g to12.0 g of sodium oxybate; and wherein the formulation is designed to beorally administered once-nightly to treat cataplexy in narcolepsy orexcessive daytime sleepiness (“EDS”) in narcolepsy.
 21. The formulationof claim 20, wherein: the suspending or viscosifying agent is selectedfrom the group consisting of xanthan gum, carrageenan gum, gellan gum,guar gum, sodium alginate, calcium alginate, agar, sodium carboxymethylcellulose, microcrystalline cellulose, hydroxyethyl cellulose,hydroxypropylmethyl cellulose, and mixtures thereof; and the acidifyingagent is selected from the group consisting of malic acid, citric acid,tartaric acid, adipic acid, boric acid, maleic acid, phosphoric acid,ascorbic acid, oleic acid, capric acid, caprylic acid, and benzoic acid.22. The formulation of claim 20, wherein: the suspending or viscosifyingagent is a mixture of xanthan gum, carrageenan gum, andhydroxyethylcellulose, or a mixture of xanthan gum and carrageenan gum,and the acidifying agent is malic acid or tartaric acid.
 23. Theformulation of claim 20, wherein the formulation further comprises alubricant or glidant selected from the group consisting of magnesiumstearate, calcium stearate, zinc stearate, glyceryl monostearate,glyceryl palmitostearate, glycerol behenate, sodium stearyl fumarate,talc, and colloidal silicon dioxide.
 24. The formulation of claim 20,wherein the formulation is a dry particulate formulation or a powderedformulation.
 25. The formulation of claim 20, wherein the formulationcomprises 4.5 g, 6.0 g, 7.5 g, or 9.0 g of gamma-hydroxybutyrate. 26.The formulation of claim 20, wherein the formulation comprisesgamma-hydroxybutyrate in the form of sodium oxybate.
 27. The formulationof claim 20, wherein the modified release portion comprises ahydrophobic compound having a melting point equal to or greater than 40°C.
 28. The formulation of claim 20, wherein a dose of the formulationachieves a relative bioavailability (RBA) of greater than 80% whencompared to an equal dose of an immediate release liquid solution ofsodium oxybate administered at t₀ and t_(4h) in equally divided doses,when administered approximately two hours after a standardized eveningmeal.
 29. The formulation of claim 20, wherein a dose of the formulationachieves a ratio of mean AUC_(8h) to mean AUC_(inf) of greater than 0.80when administered once approximately two hours after a standardizedevening meal.
 30. The formulation of claim 20, wherein a dose of theformulation achieves a median T_(max) within one hundred fifty minutesof the median T_(max) of half the dose of an immediate release liquidsolution of sodium oxybate, when administered approximately two hoursafter a standardized evening meal.
 31. The formulation of claim 20,wherein a dose of the formulation achieves a mean C_(6h) or mean C_(7h)greater than, and a mean C_(10h) less than, the mean C_(4h) of half thedose of an immediate release liquid solution of sodium oxybate, whenadministered approximately two hours after a standardized evening meal.32. The formulation of claim 20, wherein a dose of the formulationachieves a mean AUC_(inf) of greater than 80% of the mean AUC_(inf)provided by an equal dose of immediate release liquid solution of sodiumoxybate administered at t₀ and t_(4h) in equally divided dosesapproximately two hours after a standardized evening meal, and a meanC_(8h) less than 95% of the mean C_(8h) provided by an equal dose ofimmediate release liquid solution of sodium oxybate administered at t₀and t_(4h) in equally divided doses approximately two hours after astandardized evening meal.
 33. The formulation of claim 20, wherein theformulation releases at least 80% of its gamma-hydroxybutyrate at threehours when tested in a dissolution apparatus 2 according to USP 38 <711>in 900 mL of 0.05M monobasic potassium phosphate buffer pH 6.8 at atemperature of 37° C. and a paddle speed of 75 rpm.
 34. The formulationof claim 20, wherein the formulation releases from 10% to 65%, of itsgamma-hydroxybutyrate at one hour and three hours when tested in adissolution apparatus 2 according to USP 38 <711> in 900 mL of 0.1Nhydrochloric acid at a temperature of 37° C. and a paddle speed of 75rpm.
 35. The formulation of claim 20, wherein the modified releaseportion releases greater than 80% of its gamma-hydroxybutyrate at threehours when tested in a dissolution apparatus 2 according to USP 38 <711>in 900 mL of 0.05M monobasic potassium phosphate buffer pH 6.8 at atemperature of 37° C. and a paddle speed of 75 rpm.
 36. The formulationof claim 20, wherein the modified release portion releases less than 20%of its gamma-hydroxybutyrate at one hour when tested in a dissolutionapparatus 2 according to USP 38 <711> in 900 mL of 0.1N hydrochloricacid at a temperature of 37° C. and a paddle speed of 75 rpm.
 37. Theformulation of claim 20, wherein the modified release portion releasesgreater than 80% of its gamma-hydroxybutyrate at three hours in adissolution test started in 750 mL of 0.1N hydrochloric acid for 2 hoursthen switched to 950 mL 0.05M monobasic potassium phosphate bufferadjusted to pH 6.8 at a temperature of 37° C. and a paddle speed of 75rpm.
 38. The formulation of claim 20, wherein the immediate releaseportion releases greater than 80% of its gamma-hydroxybutyrate at onehour when tested in a dissolution apparatus 2 according to USP 38 <711>in 900 mL of 0.1N hydrochloric acid at a temperature of 37° C. and apaddle speed of 75 rpm.